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Gu D, Sun Y, Wang J, Sun J, Lou H, Kang W. Metformin regulates ferroptosis in Skin cutaneous melanoma via ATF3/NRF2 axis. Cancer Genet 2025; 294-295:136-144. [PMID: 40318300 DOI: 10.1016/j.cancergen.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 03/24/2025] [Accepted: 04/08/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND To explore the effects of metformin on the proliferation and ferroptosis of skin cutaneous melanoma (SKCM) and its potential molecular mechanisms, providing a new theoretical basis and strategy for the treatment of cutaneous melanoma. METHODS The CCK-8 experiment was used to detect the effect of metformin on the proliferation of skin cutaneous melanoma cells. Kits were used to detect glutathione (GSH) content, reactive oxygen species (ROS), lipid peroxide (LPO), and malondialdehyde (MDA) levels to evaluate ferroptosis-related indicators. RNA-seq sequencing and related analyses were used to screen differentially expressed genes and explore their involved biological functions and signaling pathways. Western blot was used to detect the expression levels of ATF3 and NRF2 proteins and analyze the regulatory effect of metformin on the ATF3/NRF2 axis. RESULTS Metformin significantly reduced the proliferation ability of skin cutaneous melanoma cells. The treated cells showed a decrease in GSH content and an accumulation of ROS, LPO, and MDA, suggesting that ferroptosis was regulated. RNA-seq analysis found 2068 differentially expressed genes, of which 897 were up-regulated and 1171 were down-regulated. The related pathways such as iron metabolism disorders and ferroptosis were activated. After metformin treatment, the expression of ATF3 mRNA in cells increased and was positively correlated with the concentration, while the expression in SKCM tissues decreased. At the same time, the expression of ATF3 protein increased and the expression of NRF2 protein decreased, suggesting that metformin may induce ferroptosis through the ATF3/NRF2 axis. CONCLUSION Metformin can induce ferroptosis by regulating ATF3/NRF2 axis, which may be a novel strategy for improving the treatment of skin cutaneous melanoma.
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Affiliation(s)
- Da Gu
- Department of Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Yulin Sun
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China
| | - Jianghui Wang
- Department of Orthopedic Surgery, The Second People's Hospital of Dongying, Dongying, Shandong 257000, PR China
| | - Jinpeng Sun
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China
| | - Huanmin Lou
- Department of Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China.
| | - Weiting Kang
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China.
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López-Cánovas JL, Naranjo-Martínez B, Diaz-Ruiz A. Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion. Cell Oncol (Dordr) 2025; 48:161-182. [PMID: 38990489 PMCID: PMC11850423 DOI: 10.1007/s13402-024-00966-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2024] [Indexed: 07/12/2024] Open
Abstract
PURPOSE Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M). RESULTS Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death. CONCLUSION Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.
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Affiliation(s)
- Juan L López-Cánovas
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Beatriz Naranjo-Martínez
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Alberto Diaz-Ruiz
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain.
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Komza M, Chipuk JE. Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy. J Cell Physiol 2025; 240:e31441. [PMID: 39324415 PMCID: PMC11732733 DOI: 10.1002/jcp.31441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 08/21/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024]
Abstract
Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.
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Affiliation(s)
- Monika Komza
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jerry Edward Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, New York, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, The Diabetes, Obesity, and Metabolism Institute, New York, New York, USA
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Xu P, Liu M, Liu M, Shen A. Management of non-alcoholic fatty liver disease-associated hepatocellular carcinoma. Biosci Trends 2024; 18:431-443. [PMID: 39428499 DOI: 10.5582/bst.2024.01295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.
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Affiliation(s)
- Peijun Xu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Maoyun Liu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Miao Liu
- Department of Gastrointestinal Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Ai Shen
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
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Rimini M, Montes M, Amadeo E, Vitiello F, Kudo M, Tada T, Suda G, Shimose S, Lonardi S, Finkelmeier F, Salani F, Antonuzzo L, Marra F, Iavarone M, Cabibbo G, Foschi FG, Silletta M, Sacco R, Rapposelli IG, Scartozzi M, Nicoletta P, Aldrighetti L, Persano M, Camera S, Rossari F, Foti S, Kumada T, Hiraoka A, Iwamoto H, Rizzato MD, Himmelsbach V, Masi G, Corradi M, Celsa C, Fabio C, Frassineti GL, Cascinu S, Casadei-Gardini A, Presa J. Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab. Sci Rep 2024; 14:20200. [PMID: 39215078 PMCID: PMC11364777 DOI: 10.1038/s41598-024-70928-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
- Vita-Salute University San Raffaele, Milan, Italy
| | | | - Elisabeth Amadeo
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Francesco Vitiello
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Higashiosaka, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan
| | - Sara Lonardi
- Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Fabian Finkelmeier
- Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Francesca Salani
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | | | - Marianna Silletta
- Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Puglia, Italy
| | | | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Pella Nicoletta
- Department of Oncology, ASUFC University Hospital, Udine, Italy
| | - Luca Aldrighetti
- Hepato-Biliary Surgery Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Silvia Camera
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Federico Rossari
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Silvia Foti
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Takashi Kumada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Atsushi Hiraoka
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan
| | | | - Vera Himmelsbach
- Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Gianluca Masi
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
| | - Mattia Corradi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Ciro Celsa
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Conti Fabio
- Department of Internal Medicine, Ospedale degli Infermi di Faenza, Faenza, Emilia Romagna, Italy
| | | | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
- Vita-Salute University San Raffaele, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy.
- Vita-Salute University San Raffaele, Milan, Italy.
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Liu Y, Shao K, Yang W, Shen Q, Lu M, Shao Z, Chu S, Wang Y, Wang X, Chen X, Bai J, Wu X. Phosphorylated FOXQ1, a novel substrate of JNK1, inhibits sorafenib-induced ferroptosis by activating ETHE1 in hepatocellular carcinoma. Cell Death Dis 2024; 15:395. [PMID: 38839744 PMCID: PMC11153576 DOI: 10.1038/s41419-024-06789-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant cancer with poor overall survival. The application of sorafenib is a major breakthrough in the treatment of HCC. In our study, FOXQ1 was significantly overexpressed in sorafenib-resistant HCC cells and suppressed sorafenib-induced ferroptosis. We found that phosphorylation of FOXQ1 at serine 248 is critical for the suppression of sorafenib-induced ferroptosis. Furthermore, as the upstream phosphorylation kinase of FOXQ1, JNK1, which is activated by sorafenib, can directly phosphorylate the serine 248 site of FOXQ1. Then, the phosphorylated FOXQ1 got a high affinity for the promoter of ETHE1 and activates its transcription. Further flow cytometry results showed that ETHE1 reduced intracellular lipid peroxidation and iron levels. Collectively, our study implicated the JNK1-FOXQ1-ETHE1 axis in HCC ferroptosis induced by sorafenib, providing mechanistic insight into sensitivity to sorafenib therapy of HCC.
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Affiliation(s)
- Yiwei Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Ke Shao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
- Department of General Surgery, The People's Hospital of Rugao, Affiliated Rugao Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Wendong Yang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Qi Shen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Mengru Lu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Zhiying Shao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Sufang Chu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yuming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
| | - Xiaofeng Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
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Pinto TAM, Saito HPA, Nourani CL, Ataide EC, Boin IFSF, Lourenco GJ, Lima CSP. Clinicopathological Aspects and Inflammation-Immune Markers in Alcohol and/or Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients Treated With Sorafenib. Gastroenterology Res 2024; 17:23-31. [PMID: 38463146 PMCID: PMC10923249 DOI: 10.14740/gr1689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/06/2024] [Indexed: 03/12/2024] Open
Abstract
Background Tyrosine kinase inhibitors have been used to treat hepatocellular carcinoma (HCC), but the outcomes of patients under treatment vary. Since the roles of clinicopathological aspects and markers of chronic inflammation/immune homeostasis in the outcome of HCC patients treated with sorafenib are still unclear, these were the aims of this study. Methods Patients with alcohol-induced and/or hepatitis C virus (HCV)-induced HCC (n = 182) uniformly treated with sorafenib were included in the study. Baseline clinicopathological aspects of patients were computed from the medical records. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), and systemic immune-inflammation index (SII) were obtained from the hematological exam performed before the administration of sorafenib. Overall survival (OS) was analyzed using Kaplan-Meier probabilities, log-rank test, and univariate and multivariate Cox proportional hazard ratio (HR) analyses. Results In multivariate analysis, alpha-foetoprotein (AFP) level and Child-Pugh score were predictors of OS. Patients with AFP levels higher than 157 ng/mL and Child-Pugh B or C had 1.40 (95% confidence interval (CI): 1.03 - 1.91, P = 0.03) and 1.64 (95% CI: 1.07 - 2.52, P = 0.02) more chances of evolving to death than the remaining patients, respectively. NLR, PLR, LMR, SIRI, and SII did not alter the OS of HCC patients. Conclusions AFP level and Child-Pugh score act as independent prognostic factors in patients with alcohol and/or HCV-induced HCC treated with sorafenib, but markers of chronic inflammation/immune homeostasis seem not to alter the outcome of patients with HCC induced by alcohol and/or HCV.
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Affiliation(s)
- Thiago Alexandre Martins Pinto
- Clinical Oncology Service, Department of Anesthesiology, Oncology, and Radiology, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Helena Paes Almeida Saito
- Clinical Oncology Service, Department of Anesthesiology, Oncology, and Radiology, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Carolina Lopes Nourani
- Clinical Oncology Service, Department of Anesthesiology, Oncology, and Radiology, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Elaine Cristina Ataide
- Department of Surgery, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
| | | | - Gustavo Jacob Lourenco
- Laboratory of Cancer Genetics; School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Carmen Silvia Passos Lima
- Clinical Oncology Service, Department of Anesthesiology, Oncology, and Radiology, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
- Laboratory of Cancer Genetics; School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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Vachliotis ID, Valsamidis I, Polyzos SA. Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:5306. [PMID: 37958479 PMCID: PMC10650629 DOI: 10.3390/cancers15215306] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/28/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.
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Affiliation(s)
- Ilias D. Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Gastroenterology, 424 General Military Hospital, 56429 Thessaloniki, Greece
| | - Ioannis Valsamidis
- First Department of Internal Medicine, 424 General Military Hospital, 56429 Thessaloniki, Greece;
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
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10
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Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 2023; 5:100811. [PMID: 37575883 PMCID: PMC10413159 DOI: 10.1016/j.jhepr.2023.100811] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 08/15/2023] Open
Abstract
Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.
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Affiliation(s)
- Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Eduardo H. Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Camilo J. Llamoza-Torres
- Department of Hepatology, Virgen de la Arrixaca University Hospital, Murcia, 30120, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Esteban N. Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
- WELBIO Department, WEL Research Institute, Avenue Pasteur 6, Wavre, 1300, Belgium
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11
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Cigrovski Berkovic M, Giovanardi F, Mrzljak A, Lai Q. Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis. World J Diabetes 2023; 14:1289-1300. [PMID: 37664473 PMCID: PMC10473950 DOI: 10.4239/wjd.v14.i8.1289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/24/2023] [Accepted: 05/16/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth. AIM To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients. METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted. RESULTS A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31). CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.
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Affiliation(s)
- Maja Cigrovski Berkovic
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, Zagreb 10000, Croatia
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
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12
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Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol 2023; 93:20-35. [PMID: 37149203 DOI: 10.1016/j.semcancer.2023.04.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the third leading cause of cancer-related mortality and is characterized by low survival rates. Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of HCC, whose rates are increasing, owing to the increasing prevalence of NAFLD. The pathogenesis of NAFLD-associated HCC is multifactorial: insulin resistance, obesity, diabetes and the low-grade hepatic inflammation, which characterizes NAFLD, seem to play key roles in the development and progression of HCC. The diagnosis of NAFLD-associated HCC is based on imaging in the presence of liver cirrhosis, preferably computerized tomography or magnetic resonance imaging, but liver biopsy for histological confirmation is usually required in the absence of liver cirrhosis. Some preventive measures have been recommended for NAFLD-associated HCC, including weight loss, cessation of even moderate alcohol drinking and smoking, as well as the use of metformin, statins and aspirin. However, these preventive measures are mainly based on observational studies, thus they need validation in trials of different design before introducing in clinical practice. The treatment of NAFLD should be tailored on an individual basis and should be ideally determined by a multidisciplinary team. In the last two decades, new medications, including tyrosine kinase inhibitors and immune checkpoints inhibitors, have improved the survival of patients with advanced HCC, but trials specifically designed for patients with NAFLD-associated HCC are scarce. The aim of this review was to overview evidence on the epidemiology and pathophysiology of NAFLD-associated HCC, then to comment on imaging tools for its appropriate screening and diagnosis, and finally to critically summarize the currently available options for its prevention and treatment.
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Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
| | - Ilias D Vachliotis
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Chartampilas
- Department of Radiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
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13
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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14
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Lin H, Yiu DCY, Chin S, Liu K, Yip TCF. Metformin in patients with hepatocellular carcinoma receiving immunotherapy. J Hepatol 2023; 78:e180-e182. [PMID: 36572351 DOI: 10.1016/j.jhep.2022.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Huapeng Lin
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Dorothy Cheuk-Yan Yiu
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Simone Chin
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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15
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Ielasi L, Tovoli F, Tonnini M, Stefanini B, Tortora R, Magini G, Sacco R, Pressiani T, Trevisani F, Garajová I, Piscaglia F, Granito A. Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:1523. [PMID: 36900314 PMCID: PMC10000514 DOI: 10.3390/cancers15051523] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/14/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.
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Affiliation(s)
- Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Matteo Tonnini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Raffaella Tortora
- Liver Unit, Department of Transplantation, Cardarelli Hospital, 80131 Naples, Italy
| | - Giulia Magini
- Department of Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, 71122 Foggia, Italy
| | - Tiziana Pressiani
- Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Semeiotica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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16
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Pugliese N, Alfarone L, Arcari I, Giugliano S, Parigi TL, Rescigno M, Lleo A, Aghemo A. Clinical features and management issues of NAFLD-related HCC: what we know so far. Expert Rev Gastroenterol Hepatol 2023; 17:31-43. [PMID: 36576057 DOI: 10.1080/17474124.2023.2162503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is replacing viral hepatitis as the leading cause of chronic liver disease and hepatocellular carcinoma (HCC) in many Western countries. NAFLD-associated HCC usually affects older patients with multiple comorbidities, frequently develops in the absence of cirrhosis, and is often diagnosed later with worse chance of survival. The worse prognosis is also due to limited surveillance strategies and a lower efficacy of standard treatments. AREAS COVERED We evaluate the available literature to understand the current surveillance strategies and treatment limitations in the workup of NAFLD-associated HCC, focusing on the differences with HCC associated with other liver diseases. EXPERT OPINION In this review we discuss epidemiology and risk factors for HCC in NAFLD patients and address key HCC surveillance and management issues. Although most data are still preliminary, the detection of non-cirrhotic NAFLD patients at increased risk for HCC and the potential adoption of novel screening tools could lead to accurate and suitable HCC surveillance and management strategies for NAFLD patients.
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Affiliation(s)
- Nicola Pugliese
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ludovico Alfarone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia Giugliano
- Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | | | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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17
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Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology 2022; 76:1880-1897. [PMID: 35239194 PMCID: PMC9790535 DOI: 10.1002/hep.32439] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Ariel Jaffe
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Rachel Perry
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Section of EndocrinologyDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Mario Strazzabosco
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
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18
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Wen J, Yi Z, Chen Y, Huang J, Mao X, Zhang L, Zeng Y, Cheng Q, Ye W, Liu Z, Liu F, Liu J. Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials. BMC Med 2022; 20:402. [PMID: 36280839 PMCID: PMC9594974 DOI: 10.1186/s12916-022-02599-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42022324672.
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Affiliation(s)
- Jie Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuyao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xueyi Mao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Zeng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenrui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Jingfang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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19
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Metformin administration is associated with enhanced response to transarterial chemoembolization for hepatocellular carcinoma in type 2 diabetes patients. Sci Rep 2022; 12:14482. [PMID: 36008432 PMCID: PMC9411109 DOI: 10.1038/s41598-022-18341-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 08/09/2022] [Indexed: 12/09/2022] Open
Abstract
Transarterial chemoembolization (TACE) is often used as a locoregional therapy for early hepatocellular carcinoma (HCC) when local ablation or resection are not feasible, but incomplete response and recurrence are commonly observed. In this study, we sought to determine the association between metformin administration and TACE outcomes for single nodular HCC in patients with type 2 diabetes mellitus (T2DM). The retrospective cohort analysis included 164 T2DM patients with single nodular HCC who underwent TACE as an initial treatment, and 91 were exposed to metformin before and after TACE. Propensity score (PS) matching was used to balance covariates. Logistic regression analysis was used to determine the predictors of tumor response after TACE, and Cox regression analysis assessed independent predictors of local tumor recurrence (LTR) in patients with complete response after TACE. Metformin use was associated with significantly higher objective response rate (ORR) in the overall and PS-matched cohort (79.1% vs. 60.3 and 78.7% vs. 57.5%; p = 0.008 and p = 0.029, respectively). Logistic regression analysis showed that metformin use was an independent predictor of ORR in all and PS-matched patients (odds ratio = 2.65 and 3.06; p = 0.016 and 0.034, respectively). Cox regression analysis showed metformin administration was an independent predictor for lower LTR in all and PS-matched patients (hazard ratio = 0.28 and 0.27; p = 0.001 and 0.007, respectively). Metformin administration is associated with better initial response and lower local recurrence after TACE for single nodular HCC in T2DM.
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Mattos ÂZ, Debes JD, Vogel A, Arrese M, Revelo X, Pase THS, Manica M, Mattos AA. Non-alcoholic fatty liver disease-related hepatocellular carcinoma: Is there a role for immunotherapy? World J Gastroenterol 2022; 28:3595-3607. [PMID: 36161041 PMCID: PMC9372815 DOI: 10.3748/wjg.v28.i28.3595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/26/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common cancers and it is a major cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD) affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC. The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood. However, metabolic, fibrogenic, oncogenic, inflammatory and immunological pathways seem to be involved. First-line therapy of advanced HCC has recently undergone major changes, since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib. Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy. However, initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease, which seems to be particularly important in NAFLD-related HCC, as these tumors might not benefit from it. This article will review the mechanisms of NAFLD-related hepatocarcinogenesis, with an emphasis on its immune aspects, the efficacy of traditional systemic therapy for advanced NAFLD-related HCC, and the most recent data on the role of immunotherapy for this specific group of patients, showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.
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Affiliation(s)
- Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Jose D Debes
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam 999025, Netherlands
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine and Center for Aging and Regeneration, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
| | - Xavier Revelo
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, United States
| | - Tales Henrique S Pase
- Internal Medicine Unit, Irmandade Santa Casa de Miser-icórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Muriel Manica
- Internal Medicine Unit, Irmandade Santa Casa de Miser-icórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90050-170, Brazil
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Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23158083. [PMID: 35897659 PMCID: PMC9329836 DOI: 10.3390/ijms23158083] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
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22
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Lamm R, Altshuler PJ, Patel K, Shaheen O, Amante AP, Civan J, Maley W, Frank A, Ramirez C, Glorioso J, Shah A, Dang H, Bodzin AS. Reduced Rates of Post-Transplant Recurrent Hepatocellular Carcinoma in Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis. Transpl Int 2022; 35:10175. [PMID: 35865863 PMCID: PMC9294152 DOI: 10.3389/ti.2022.10175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 06/13/2022] [Indexed: 11/13/2022]
Abstract
Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC—1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years post-transplant was lower in NASH compared to non-NASH patients (5.80 vs. 9.41%, p = 0.01). Recurrence-free survival, however, was similar at 5 years between groups. Patients with NASH-related HCC were less likely to have post-transplant recurrence than their non-NASH counterparts, although recurrence-free survival was similar at 5 years.
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Affiliation(s)
- Ryan Lamm
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Peter J. Altshuler
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Keyur Patel
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Osama Shaheen
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Angel Paulo Amante
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Jesse Civan
- Department of Gastroenterology, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Warren Maley
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Adam Frank
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Carlo Ramirez
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Jaime Glorioso
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Ashesh Shah
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
| | - Adam S. Bodzin
- Department of Surgery, Thomas Jefferson University Hospital, Jefferson University Hospitals, Philadelphia, PA, United States
- *Correspondence: Adam S. Bodzin,
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Cao JZ, Wang ZG, Yu J, Tao YP, Yang Y, Liu H, Zhou WP, Lu J, Huang Q. Antidiabetic treatment improves prognosis after radical resection in hepatocellular carcinoma patients with diabetes mellitus: a retrospective cohort study from 2000 to 2013. J Gastrointest Oncol 2022; 13:1330-1339. [PMID: 35837203 PMCID: PMC9274028 DOI: 10.21037/jgo-22-478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/14/2022] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND It remains unclear whether diabetic medications, such as metformin and insulin, affect the post-liver resection prognosis of hepatocellular carcinoma (HCC) patients complicated with diabetes mellitus (DM). This study try to find out the prognostic factors in HCC patients with DM and provide a better antidiabetic therapy after liver resection. METHODS Patients presenting with HCC complicated with DM undergoing liver resection were enrolled in this study. They were examined and followed up every 3-6 months after surgery. Patients were divided into the antidiabetic treatment group and no antidiabetic treatment group according to whether they received medications for diabetes or not. Then patients in the antidiabetic treatment group were further divided into insulin group, metformin group, insulin plus metformin group and others group, according to the medications they received. Overall survival (OS) and recurrence-free survival (RFS) were compared among two groups and four subgoups. Comparative and multivariate analyses were performed to investigate the effects of DM medication on the prognosis of these HCC patients, using Cox proportional hazards model. RESULTS The 1-, 3-, 5-, and 7-year OS rates for the antidiabetic treatment group were 87.5%, 75.5%, 48.7%, and 29.1%, respectively, and for the no antidiabetic treatment group, the OS rates were 85.4%, 57.7%, 33.6%, and 19.1%, respectively (P=0.007). The 1-, 3-, 5-, 7-year RFS rates for the antidiabetic treatment group were 76.4%, 53.5%, 28.5%, and 17.5%, respectively, and for the no antidiabetic treatment group, the RFS rates were 69.5%, 32.5%, 16.5%, and 10.7%, respectively (P=0.001). In subgroup analysis, There was no significant difference in either RFS (P=0.934) nor OS (P=0.412) among the different types of antidiabetic treatment regimens. Cox proportional hazard regression analysis revealed that tumor size (HR: 1.048), tumor number (HR: 1.626), vascular invasion (HR: 2.074, P=0.003), satellite tumor (HR: 1.592), Edmondson classification (HR: 1.468) and antidiabetic treatment (HR: 0.722) were independent prognostic factors of DFS, while tumor size (HR: 1.048), tumor number (HR: 1.779), vascular invasion (HR: 2.545), Edmondson classification (HR: 1.596) and antidiabetic treatment (HR: 0.713) were independent prognostic factors of OS. CONCLUSIONS For HCC patients with DM, antidiabetic treatment should be recommended aggressively in order to improve the surgical outcome, regardless of which antidiabetic drugs are used.
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Affiliation(s)
- Jing-Zhu Cao
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Guang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Ping Tao
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
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Foerster F, Gairing SJ, Müller L, Galle PR. NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options. J Hepatol 2022; 76:446-457. [PMID: 34555422 DOI: 10.1016/j.jhep.2021.09.007] [Citation(s) in RCA: 165] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/17/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022]
Abstract
In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment.
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Affiliation(s)
- Friedrich Foerster
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany
| | - Simon Johannes Gairing
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany
| | - Lukas Müller
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes-Gutenberg University Mainz, Germany
| | - Peter Robert Galle
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany.
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25
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Chen ML, Wu CX, Zhang JB, Zhang H, Sun YD, Tian SL, Han JJ. Transarterial chemoembolization combined with metformin improves the prognosis of hepatocellular carcinoma patients with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:996228. [PMID: 36187118 PMCID: PMC9520252 DOI: 10.3389/fendo.2022.996228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The study aims to investigate the effect of metformin on Hepatocellular carcinoma (HCC) patients with type 2 diabetes mellitus (T2DM) who received transarterial chemoembolization (TACE) for the first time. METHODS From January 2016 to December 2019, T2DM patients diagnosed with HCC in Shandong Cancer Hospital and treated with TACE were included in this retrospective study. Overall survival (OS) and Progression-free survival (PFS) were compared between patients treated with metformin and other antidiabetics. Univariate and multivariate Cox regression models were used to evaluate the independent risk factors associated with OS and PFS. And sub-analysis was performed to investigate whether metformin could give a survival advantage in each Barcelona Clinic Liver Cancer (BCLC) stage of HCC. Propensity score matched (PSM) analyses based on patient and tumor characteristics were also conducted. RESULTS A total of 123 HCC patients with T2DM underwent TACE, of which 50 (40.65%) received treatment with metformin. For the whole cohort, the median OS (42 vs 32 months, p=0.054) and PFS (12 vs 7 months, P=0.0016) were longer in the metformin group than that in the non-metformin group. Multi-analysis revealed that BCLC stage, BMI (Body Mass Index), and metformin use were independent predictors of OS. Metformin use was independently associated with recurrence. After PSM, 39 matched pairs were identified. The use of metformin was associated with a numerically longer m OS (43 vs 35 months, P=0.183) than the use of other anti-diabetics. And the difference in median PFS (13 vs 7 months, p=0.018) between the metformin group and non-metformin group remained significant. CONCLUSION The combination of transarterial chemoembolization and metformin may be associated with better OS and PFS in HCC patients with T2DM.
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Affiliation(s)
- Miao-Ling Chen
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chun-Xue Wu
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jian-Bo Zhang
- Pathology Department, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Hao Zhang
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yuan-Dong Sun
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shi-Lin Tian
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jian-Jun Han
- Interventional Medicine Center, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Jian-Jun Han, ;
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Zhang C, Liu S, Yang M. Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options. Front Endocrinol (Lausanne) 2021; 12:808526. [PMID: 35002979 PMCID: PMC8733382 DOI: 10.3389/fendo.2021.808526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which will affect more than a million people by the year 2025. However, current treatment options have limited benefits. Nonalcoholic fatty liver disease (NAFLD) is the fastest growing factor that causes HCC in western countries, including the United States. In addition, NAFLD co-morbidities including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) promote HCC development. Alteration of metabolites and inflammation in the tumor microenvironment plays a pivotal role in HCC progression. However, the underlying molecular mechanisms are still not totally clear. Herein, in this review, we explored the latest molecules that are involved in obesity, T2DM, and CVDs-mediated progression of HCC, as they share some common pathologic features. Meanwhile, several therapeutic options by targeting these key factors and molecules were discussed for HCC treatment. Overall, obesity, T2DM, and CVDs as chronic metabolic disease factors are tightly implicated in the development of HCC and its progression. Molecules and factors involved in these NAFLD comorbidities are potential therapeutic targets for HCC treatment.
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Affiliation(s)
- Chunye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, United States
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO, United States
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Ielasi L, Tovoli F, Tonnini M, Tortora R, Magini G, Sacco R, Pressiani T, Trevisani F, Sansone V, Marasco G, Piscaglia F, Granito A. Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders. Cancers (Basel) 2021; 13:6376. [PMID: 34944996 PMCID: PMC8699252 DOI: 10.3390/cancers13246376] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 02/07/2023] Open
Abstract
Case-control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child-Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543-0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.
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Affiliation(s)
- Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (F.T.); (G.M.)
| | - Matteo Tonnini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
| | - Raffaella Tortora
- Liver Unit, Department of Transplantation, Cardarelli Hospital, 80131 Naples, Italy;
| | - Giulia Magini
- Department of Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy;
| | - Rodolfo Sacco
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy;
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, 71122 Foggia, Italy
| | - Tiziana Pressiani
- Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy;
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (F.T.); (G.M.)
- Semeiotica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (F.T.); (G.M.)
- Internal Medicine and Digestive Physiopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (F.T.); (G.M.)
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.I.); (M.T.); (V.S.); (F.P.); (A.G.)
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (F.T.); (G.M.)
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Pretta A, Ziranu P, Puzzoni M, Lai E, Orsi G, Liscia N, Molinaro E, Mariani S, Riggi L, Rovesti G, Dubois M, Migliari M, Persano M, Saba G, Impera V, Musio F, Batzella E, Demurtas L, Pusceddu V, Astara G, Faloppi L, Casadei Gardini A, Andrikou K, Cascinu S, Scartozzi M. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus. TUMORI JOURNAL 2021; 107:550-555. [PMID: 33243068 DOI: 10.1177/0300891620976945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Molinaro
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Laura Riggi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Erich Batzella
- Department of Statistical Science, University of Padova, Padova, Veneto, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Macerata General Hospital, Macerata, Italy
| | - Andrea Casadei Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
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Comparison of prognostic models in advanced hepatocellular carcinoma patients undergoing Sorafenib: A multicenter study. Dig Liver Dis 2021; 53:1011-1019. [PMID: 33353858 DOI: 10.1016/j.dld.2020.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sorafenib is the gold standard therapy for the advanced hepatocellular carcinoma (HCC). No scoring/staging is universally accepted to predict the survival of these patients. AIMS To evaluate the accuracy of the available prognostic models for HCC to predict the survival of advanced HCC patients treated with Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. METHODS The performance of several prognostic scores was assessed through a Cox regression-model evaluating the C-index and the Akaike Information Criterion (AIC). RESULTS Data of 1129 patients were analyzed. The mean age of patients was 61.6 years, and 80.8% were male. During a median follow-up period of 13 months, 789 patients died. The median period of Sorafenib administration was 4 months. All the prognostic scores were able to predict the overall survival (p<0.001) at univariate analysis, except the Albumin-Bilirubin score. The Italian Liver Cancer score (CLIP) yielded the highest accuracy (C-index 0.604, AIC 9898), followed by the ITA.LI.CA. prognostic score (C-index 0.599, AIC 9915). CONCLUSIONS The CLIP score had the highest accuracy in predicting the overall survival of HCC patients treated with Sorafenib, although its performance remained poor. Further studies are needed to refine the current ability to predict the outcome of HCC patients undergoing Sorafenib.
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Harati R, Vandamme M, Blanchet B, Bardin C, Praz F, Hamoudi RA, Desbois-Mouthon C. Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells. Mol Pharmacol 2021; 100:32-45. [PMID: 33990407 DOI: 10.1124/molpharm.120.000223] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/09/2021] [Indexed: 01/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.
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Affiliation(s)
- Rania Harati
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Marc Vandamme
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Benoit Blanchet
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christophe Bardin
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Françoise Praz
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Rifat Akram Hamoudi
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
| | - Christèle Desbois-Mouthon
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.)
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Cho YY, Yu SJ, Lee HW, Kim DY, Kang W, Paik YH, Sung PS, Bae SH, Park SC, Doh YS, Kim KM, Jang ES, Kim IH, Kim W, Kim YJ. Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study. J Hepatocell Carcinoma 2021; 8:613-623. [PMID: 34169044 PMCID: PMC8219232 DOI: 10.2147/jhc.s304439] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIM Sorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment. METHODS This multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles. RESULTS The patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001). CONCLUSION This large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.
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Affiliation(s)
- Young Youn Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Pil Soo Sung
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Su Cheol Park
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Young Seok Doh
- Department of Internal Medicine, Eulji University Hospital, Daejeon, Korea
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Sun Jang
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Cheongju-si, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Casadei-Gardini A, Rovesti G, Dadduzio V, Vivaldi C, Lai E, Lonardi S, Fornaro L, Pretta A, Zagonel V, Bernardini L, Astara G, D'Amico FE, Masi G, Rimini M, Scartozzi M, Cascinu S. Impact of Aspirin on clinical outcome in advanced HCC patients receiving sorafenib and regorafenib. HPB (Oxford) 2021; 23:915-920. [PMID: 33191108 DOI: 10.1016/j.hpb.2020.09.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/25/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib. METHODS 304 patients with HCC,consecutively treated with sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02). CONCLUSION Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.
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Affiliation(s)
- Andrea Casadei-Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy.
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 4121, Modena, Italy
| | - Vincenzo Dadduzio
- Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Caterina Vivaldi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via savi 10, 56126, Pisa PI, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Lorenzo Fornaro
- U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, via Roma 67, 56126 Pisa, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Laura Bernardini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via savi 10, 56126, Pisa PI, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Francesco E D'Amico
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via savi 10, 56126, Pisa PI, Italy
| | - Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 4121, Modena, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy
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Kegasawa T, Sakamori R, Maesaka K, Yamada R, Tahata Y, Urabe A, Kodama T, Hikita H, Imanaka K, Ohkawa K, Hiramatsu N, Oshita M, Yamada Y, Inada M, Yakushijin T, Imai Y, Tatsumi T, Takehara T. Lower Serum Sodium Levels Are Associated with the Therapeutic Effect of Sorafenib on Hepatocellular Carcinoma. Dig Dis Sci 2021; 66:1720-1729. [PMID: 32556820 DOI: 10.1007/s10620-020-06380-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/30/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND AND AIM Although the serum sodium level has been reported to be a prognostic and predictive marker for the therapeutic effects of lung cancer and renal cell carcinoma treated with molecular targeted therapy, the serum sodium level has not been investigated in hepatocellular carcinoma (HCC) patients treated with sorafenib. The aim of our analysis was to assess the prognostic role of serum sodium levels in these patients. METHODS We retrospectively analyzed 341 HCC patients treated with sorafenib between 2009 and 2012 in our hospital and other related institutions. RESULTS A total of 178 patients were enrolled in this study. The median age was 72 years (44-88), and 148 patients (83%) were male. The median overall survival (OS) was 12.9 months, and the median time to progression (TTP) was 3.1 months. Hyponatremia (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.26-2.52), a lower sodium level (HR 1.57, 95% CI 1.07-2.80), and a high level of α-fetoprotein (AFP) (≥ 200 ng/mL) (HR 1.78, 95% CI 1.26-2.52) were independent prognostic factors for TTP. We also categorized the patients into three groups according to serum sodium and AFP levels: Group A (n = 39) (serum sodium > 140 mEq/L, AFP < 200 ng/mL), Group C (n = 58) (serum sodium ≤ 140 mEq/L, AFP ≥ 200 ng/mL), and Group B (n = 81) (other patients). Significantly longer TTP and OS were observed in the following order: Groups A, C, and B. CONCLUSION Serum sodium levels are associated with the effectiveness of sorafenib. The serum sodium level can predict the therapeutic effect of sorafenib in advanced HCC patients.
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Affiliation(s)
- Tadashi Kegasawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuki Maesaka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | | | | | | | | | | | - Masami Inada
- Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan
| | | | | | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms. Cancer Lett 2021; 510:1-12. [PMID: 33857528 DOI: 10.1016/j.canlet.2021.03.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/21/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022]
Abstract
Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
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Geh D, Anstee QM, Reeves HL. NAFLD-Associated HCC: Progress and Opportunities. J Hepatocell Carcinoma 2021; 8:223-239. [PMID: 33854987 PMCID: PMC8041650 DOI: 10.2147/jhc.s272213] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.
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Affiliation(s)
- Daniel Geh
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
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36
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Casadei-Gardini A, Filippi R, Rimini M, Rapposelli IG, Fornaro L, Silvestris N, Aldrighetti L, Aimar G, Rovesti G, Bartolini G, Vivaldi C, Brunetti O, Sperti E, La Face R, Ratti F, Andrikou K, Valgiusti M, Bernardini L, Argentiero A, Fenocchio E, Frassineti GL, Cesario S, Giovannelli F, Quarà V, Leone F, Cascinu S. Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients. Oncology 2021; 99:292-299. [PMID: 33626532 DOI: 10.1159/000512796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/03/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIMS In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications. METHODS All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics. RESULTS A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016). CONCLUSIONS Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.
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Affiliation(s)
| | - Roberto Filippi
- Department of Oncology, University of Turin, Turin, Italy.,Centro Oncologico Ematologico Subalpino, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Margherita Rimini
- Unit of Oncology, Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Lorenzo Fornaro
- U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Nicola Silvestris
- IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.,Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, Milan, Italy
| | - Giacomo Aimar
- Department of Oncology, University of Turin, Turin, Italy.,Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Giulia Rovesti
- Unit of Oncology, Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Bartolini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Caterina Vivaldi
- U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Elisa Sperti
- Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy
| | - Rosa La Face
- Department of Oncology, University of Turin, Turin, Italy.,Centro Oncologico Ematologico Subalpino, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, Milan, Italy
| | - Kalliopi Andrikou
- Unit of Oncology, Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Laura Bernardini
- U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Elisabetta Fenocchio
- Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Silvia Cesario
- U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesco Giovannelli
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Virginia Quarà
- Department of Oncology, University of Turin, Turin, Italy.,Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Francesco Leone
- Department of Oncology, Azienda Sanitaria Locale di Biella, Ponderano, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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37
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Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr 2021; 10:59-75. [PMID: 33575290 DOI: 10.21037/hbsn.2019.08.08] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
Importance Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC. Objective To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases. Evidence Review MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included. Findings Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. Conclusions and Relevance This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.
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Affiliation(s)
- Daniel Geh
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Derek M Manas
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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38
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Donisi C, Puzzoni M, Ziranu P, Lai E, Mariani S, Saba G, Impera V, Dubois M, Persano M, Migliari M, Pretta A, Liscia N, Astara G, Scartozzi M. Immune Checkpoint Inhibitors in the Treatment of HCC. Front Oncol 2021; 10:601240. [PMID: 33585218 PMCID: PMC7874239 DOI: 10.3389/fonc.2020.601240] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.
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Affiliation(s)
- Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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39
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Tang Z, Tang N, Jiang S, Bai Y, Guan C, Zhang W, Fan S, Huang Y, Lin H, Ying Y. The Chemosensitizing Role of Metformin in Anti-Cancer Therapy. Anticancer Agents Med Chem 2021; 21:949-962. [PMID: 32951587 DOI: 10.2174/1871520620666200918102642] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/23/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anti-cancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anti-cancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of Cancer Stem Cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse Epithelial to Mesenchymal Transition (EMT), and Multidrug Resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1 α, and Mitogen- Activated Protein Kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and Pyruvate Kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.>.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Nan Tang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shanxi Provincial People's Hospital, Xian 710000, China
| | - Yangjinming Bai
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Chenxi Guan
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wansi Zhang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Shipan Fan
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China
| | - Yonghong Huang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
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40
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Hsieh MH, Kao TY, Hsieh TH, Kao CC, Peng CY, Lai HC, Chuang PH, Kao JT. Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib. PLoS One 2020; 15:e0244293. [PMID: 33382703 PMCID: PMC7775090 DOI: 10.1371/journal.pone.0244293] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/08/2020] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND & AIMS It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. METHODS From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. RESULTS DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). CONCLUSIONS Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.
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Affiliation(s)
- Ming-Han Hsieh
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tzu-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Hui Hsieh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Chi Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jung-Ta Kao
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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41
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Lai E, Astara G, Ziranu P, Pretta A, Migliari M, Dubois M, Donisi C, Mariani S, Liscia N, Impera V, Persano M, Tolu S, Balconi F, Pinna G, Spanu D, Pireddu A, Saba G, Camera S, Musio F, Puzzoni M, Pusceddu V, Madeddu C, Casadei Gardini A, Scartozzi M. Introducing immunotherapy for advanced hepatocellular carcinoma patients: Too early or too fast? Crit Rev Oncol Hematol 2020; 157:103167. [PMID: 33271389 DOI: 10.1016/j.critrevonc.2020.103167] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Simona Tolu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Annagrazia Pireddu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Silvia Camera
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
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Li X, Chen W, Liu K, Zhang S, Yang R, Liu K, Li D, Huang Y. Oridonin Sensitizes Hepatocellular Carcinoma to the Anticancer Effect of Sorafenib by Targeting the Akt Pathway. Cancer Manag Res 2020; 12:8081-8091. [PMID: 32982405 PMCID: PMC7494228 DOI: 10.2147/cmar.s257482] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/18/2020] [Indexed: 01/07/2023] Open
Abstract
Background Oridonin is the core bioactive component of Rabdosia rubescens, a traditional Chinese herbal medicine used in the treatment of hepatoma. Sorafenib, a targeted therapeutic agent for advanced hepatocellular carcinoma (HCC), has recently been shown to exert limited clinical effects. However, few studies have focused on the synergistic effect of these two drugs on hepatocellular carcinoma. Methods We treated different HCC cell lines with different concentrations of oridonin and sorafenib and assessed the viability by using MTT assays and examined proliferation, migration, invasion and apoptosis after cotreatment of HepG2 cells with 20 μM oridonin and 5 μM sorafenib via colony formation assays, Transwell assays and flow cytometry. Regulatory effects were measured by Western blotting. The in vivo synergistic effect was confirmed through xenograft tumor models, and tumor tissues were analyzed by immunohistochemistry. Results The inhibitory effects of oridonin and sorafenib cotreatment on HCC cells were stronger than those of either drug alone. In addition, combined treatment with the two drugs synergistically inhibited epithelial–mesenchymal transition and the Akt pathway but not NF-κB or MAPK signaling. Akt phosphorylation by SC79 reversed the inhibitory effects of the combined treatment. Synergistic inhibition was equally observed in vivo. Conclusion Oridonin combined with sorafenib synergistically inhibited proliferation, migration, invasion, and epithelial–mesenchymal transition and induced apoptosis by targeting the Akt pathway but not NF-κB or MAPK signaling.
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Affiliation(s)
- Xuguang Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Weirun Chen
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Kaihang Liu
- Department of General Practice, The People's Hospital of Longhua, Shenzhen, Guangdong Province, People's Republic of China
| | - Sheng Zhang
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Ru Yang
- Department of General Practice, Women & Children Health Institute Futian Shenzhen, Shenzhen, Guangdong Province, People's Republic of China
| | - Kairui Liu
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
| | - Dateng Li
- Department of Statistical Science, Southern Methodist University, Dallas, TX 75275, USA
| | - Youxing Huang
- Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People's Republic of China
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Fu K, Yang X, Wu H, Gong J, Li X. Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma. Oncol Lett 2020; 20:265. [PMID: 32989399 PMCID: PMC7517629 DOI: 10.3892/ol.2020.12128] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 08/24/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a common disease, but its effect on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) has not been reported. The aim of the present study was to explore the prognostic significance of diabetes in patients with ICC treated with hepatectomy and to clarify the role of pyruvate kinase M2 (PKM2). A consecutive retrospective cohort of 110 patients with ICC (28 with DM and 82 without DM) who underwent therapeutic hepatectomy was evaluated between January 2006 and January 2011. The clinicopathological characteristics of the two groups and the differences between overall survival (OS) and recurrence-free survival (RFS) were analyzed. The Cox proportional hazards model was further used to identify independent prognostic predictors. PKM2 expression was measured using immunohistochemical staining in tissues collected, after obtaining informed consent. Patients with ICC with DM exhibited significantly lower OS and RFS rates at 1, 3 and 5 years compared with patients with ICC without DM. Cox multivariate analysis revealed that DM was an independent predictor of poor OS and RFS. Additionally, high PKM2 expression was significantly higher in patients with ICC with DM compared with that in patients without DM. Overall, DM was associated with significantly lower OS and RFS rates in patients with ICC. The underlying biological rationale may be attributed to the higher PKM2 expression rate.
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Affiliation(s)
- Kui Fu
- Department of Hepatobiliary Surgery, Traditional Chinese Medicine Hospital of Chongqing Dianjiang, Chongqing 408300, P.R. China
| | - Xiaoli Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xiuyun Li
- Department of Hepatobiliary Surgery, Traditional Chinese Medicine Hospital of Chongqing Dianjiang, Chongqing 408300, P.R. China
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Yan X, Qu X, Tian R, Xu L, Jin X, Yu S, Zhao Y, Ma J, Liu Y, Sun L, Su J. Hypoxia-induced NAD + interventions promote tumor survival and metastasis by regulating mitochondrial dynamics. Life Sci 2020; 259:118171. [PMID: 32738362 DOI: 10.1016/j.lfs.2020.118171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/16/2020] [Accepted: 07/27/2020] [Indexed: 02/08/2023]
Abstract
Hypoxia, an important feature of the tumor microenvironment, is responsible for the chemo-resistance and metastasis of malignant solid tumors. Recent studies indicated that mitochondria undergo morphological transitions as an adaptive response to maintain self-stability and connectivity under hypoxic conditions. NAD+ may not only provide reducing equivalents for biosynthetic reactions and in determining energy production, but also functions as a signaling molecule in mitochondrial dynamics regulation. In this review, we describe the upregulated KDAC deacetylase expression in the mitochondria and cytoplasm of tumor cells that results from sensing the changes in NAD+ to control mitochondrial dynamics and distribution, which is responsible for survival and metastasis in hypoxia.
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Affiliation(s)
- Xiaoyu Yan
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xianzhi Qu
- Department of Hepatobiliary & Pancreatic Surgery, The Second Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, China
| | - Rui Tian
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Long Xu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xue Jin
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Sihang Yu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yuanxin Zhao
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jiaoyan Ma
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yanan Liu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Liankun Sun
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
| | - Jing Su
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
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Karbownik A, Miedziaszczyk M, Grabowski T, Stanisławiak-Rudowicz J, Jaźwiec R, Wolc A, Grześkowiak E, Szałek E. In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol. Biomed Pharmacother 2020; 130:110530. [PMID: 32712531 DOI: 10.1016/j.biopha.2020.110530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/07/2020] [Accepted: 07/11/2020] [Indexed: 02/08/2023] Open
Abstract
Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic μ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (Cmax) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC0-∞) increased 1.5-fold. The tapentadol glucuronide Cmax increased 5.3-fold and whereas its AUC0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC0-∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR Cmax 1.9-fold, whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide Cmax increased 1.9-fold whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC0-t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too.
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Affiliation(s)
- Agnieszka Karbownik
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861, Poznań, Poland.
| | - Miłosz Miedziaszczyk
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861, Poznań, Poland
| | - Tomasz Grabowski
- Polpharma Biologics SA, Trzy Lipy 3 Str., 80-172, Gdańsk, Poland
| | | | - Radosław Jaźwiec
- Institute of Biochemistry and Biophysics PAS, Laboratory of Mas Spectromery, Polish Academy of Sciences, 5A Pawińskiego Str, 02-106, Warsaw, Poland
| | - Anna Wolc
- Department of Animal Science, Iowa State University, 239E Kildee Hall, Ames, IA, 50011, USA; Hy-Line International, 2583 240th Street, Dallas Center, IA, 50063, USA
| | - Edmund Grześkowiak
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861, Poznań, Poland
| | - Edyta Szałek
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861, Poznań, Poland
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Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B. Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target. Theranostics 2020; 10:8315-8342. [PMID: 32724473 PMCID: PMC7381741 DOI: 10.7150/thno.45922] [Citation(s) in RCA: 292] [Impact Index Per Article: 58.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/08/2020] [Indexed: 02/05/2023] Open
Abstract
Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.
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Karbownik A, Szkutnik-Fiedler D, Czyrski A, Kostewicz N, Kaczmarska P, Bekier M, Stanisławiak-Rudowicz J, Karaźniewicz-Łada M, Wolc A, Główka F, Grześkowiak E, Szałek E. Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats. Pharmaceutics 2020; 12:pharmaceutics12070600. [PMID: 32605304 PMCID: PMC7408095 DOI: 10.3390/pharmaceutics12070600] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib−metformin and sorafenib−atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2−hydroxy atorvastatin (p = 0.0239) and 4−hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.
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Affiliation(s)
- Agnieszka Karbownik
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
- Correspondence: ; Tel.: +48-61854-60000
| | - Danuta Szkutnik-Fiedler
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Andrzej Czyrski
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Natalia Kostewicz
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Paulina Kaczmarska
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Małgorzata Bekier
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | | | - Marta Karaźniewicz-Łada
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Anna Wolc
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA;
- Hy-Line International, Research and Development, Dallas Center, IA 50063, USA
| | - Franciszek Główka
- Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, 60-781 Poznań, Poland; (A.C.); (M.K.-Ł.); (F.G.)
| | - Edmund Grześkowiak
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
| | - Edyta Szałek
- Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 61-861 Poznań, Poland; (D.S.-F.); (N.K.); (P.K.); (M.B.); (E.G.); (E.S.)
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Alghamdi MA, Amaro CP, Lee-Ying R, Sim HW, Samwi H, Chan KK, Knox JJ, Ko YJ, Swiha M, Batuyong E, Romagnino A, Cheung WY, Tam VC. Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: Results from a Canadian Multicenter Database. Cancer Med 2020; 9:4918-4928. [PMID: 32529797 PMCID: PMC7367626 DOI: 10.1002/cam4.3228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022] Open
Abstract
Background Sorafenib has been shown to improve survival in patients with advanced hepatocellular carcinoma (HCC), however, full dose can be difficult to tolerate. The aim of this study was to determine whether sorafenib starting dose and mean dose intensity affect survival. Methods Patients treated with sorafenib for HCC from January 2008 to July 2016 in several Canadian provinces were included and retrospectively analyzed. The primary end point was overall survival (OS) of patients starting on sorafenib full dose compared to reduced dose. Secondary analysis compared OS with different mean dose‐intensity groups. Survival outcomes were assessed with Kaplan‐Meier curves and Cox proportional hazards models. A propensity score analysis was performed to account for treatment bias and confounding. Results Of 681 patients included, sorafenib was started at full dose in 289 patients (42%). Median survival for starting full and reduced dose was 9.4 months and 8.9 months (P = .15) respectively. After propensity score matching and adjusting for potential confounders there was still no difference in survival (HR 0.8, 95% CI, 0.61‐1.06, P = .12). Almost half of the patients (45%) received a dose intensity < 50%. Median survival for mean dose intensity > 75%, 50%‐75%, and < 50% were 9.5 months, 12.9 months, and 7.1 months (P = .005) respectively. In multivariable models, starting dose(HR 1.16, 95% CI 0.93‐1.44, P = .180) and mean dose intensity were not associated with survival. Conclusions Starting HCC patients on a reduced dose of sorafenib compared to full dose may not compromise survival. Mean dose‐intensity of sorafenib may also not affect survival.
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Affiliation(s)
- Mohammed A Alghamdi
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.,College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Carla P Amaro
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
| | - Richard Lee-Ying
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
| | - Hao-Wen Sim
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Haider Samwi
- St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Kelvin K Chan
- Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.,Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada
| | - Jennifer J Knox
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Mina Swiha
- University of Western Ontario, London, ON, Canada.,Menoufia University, Shebin El Kom, Egypt
| | - Eugene Batuyong
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
| | | | - Winson Y Cheung
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
| | - Vincent C Tam
- Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
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The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5:87. [PMID: 32532960 PMCID: PMC7292831 DOI: 10.1038/s41392-020-0187-x] [Citation(s) in RCA: 655] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/14/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
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Caputo F, Dadduzio V, Tovoli F, Bertolini G, Cabibbo G, Cerma K, Vivaldi C, Faloppi L, Rizzato MD, Piscaglia F, Celsa C, Fornaro L, Marisi G, Conti F, Silvestris N, Silletta M, Lonardi S, Granito A, Stornello C, Massa V, Astara G, Delcuratolo S, Cascinu S, Scartozzi M, Casadei-Gardini A. The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib. PLoS One 2020; 15:e0232449. [PMID: 32379785 PMCID: PMC7205300 DOI: 10.1371/journal.pone.0232449] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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Affiliation(s)
- Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Dadduzio
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Francesco Tovoli
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Krisida Cerma
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Luca Faloppi
- Medical Oncology Unit, Macerata General Hospital, Macerata, Italy
| | - Mario Domenico Rizzato
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabio Piscaglia
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | - Ciro Celsa
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | | | - Giorgia Marisi
- Medical Oncology Unit IRCSS-IRST Meldola, Meldola, Italy
| | - Fabio Conti
- Department of Internal Medicine, Degli Infermi Hospital, Faenza, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Marianna Silletta
- Medical Oncology Department, Campus Biomedico, University of Rome, Rome, Italy
| | - Sara Lonardi
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Alessandro Granito
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | | | - Giorgio Astara
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Sabina Delcuratolo
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
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