1
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Lee D, Liew MS, Fourlanos S, Choi J. Metformin use and pancreatic ductal adenocarcinoma outcomes: a narrative review. ANZ J Surg 2025; 95:313-320. [PMID: 39840695 DOI: 10.1111/ans.19405] [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: 10/07/2024] [Revised: 01/04/2025] [Accepted: 01/09/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND Metformin is a diabetes medication with anti-mitotic properties. A narrative review was performed to investigate people using metformin and the risk of developing pancreatic ductal adenocarcinoma (PDAC) as well as survival outcomes in established PDAC. METHODS Relevant studies on metformin use and PDAC were retrieved from PubMed including observational studies on metformin and the risk of developing PDAC and survival outcomes in PDAC, and randomized controlled trials of metformin as a treatment in PDAC. RESULTS Of the 367 studies searched, 26 studies fulfilled the criteria for this review. Metformin was not consistently associated with a reduced risk of developing PDAC. However, metformin use, especially higher cumulative doses, in some studies was associated with longer survival in patients with established PDAC, especially in the subgroup with resectable PDAC. Metformin use was not associated with longer survival in more advanced (non-resectable metastatic) PDAC. CONCLUSION Metformin was not consistently associated with a reduced risk of developing PDAC. Metformin may be associated with overall survival benefits in patients with PDAC including the resectable PDAC subgroup but not in the metastatic PDAC subgroup. The evidence to date does not support the routine use of metformin as an adjuvant therapy for advanced PDAC.
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Affiliation(s)
- Dooyeon Lee
- Department of Surgery, Western Health, St. Albans, Victoria, Australia
| | - Mun Sem Liew
- Victorian Oncology Care, St John of God Specialist Centre, Berwick, Victoria, Australia
| | - Spiros Fourlanos
- Department of Diabetes & Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Julian Choi
- Department of Surgery, Western Health, St. Albans, Victoria, Australia
- Department of Surgery, University of Melbourne, Parkville, Victoria, Australia
- Clinical Institute General Surgery and Gastroenterology, Epworth Healthcare, Richmond, Victoria, Australia
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2
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Leddy E, Attachaipanich T, Chattipakorn N, Chattipakorn SC. Investigating the effect of metformin on chemobrain: Reports from cells to bedside. Exp Neurol 2025; 385:115129. [PMID: 39733854 DOI: 10.1016/j.expneurol.2024.115129] [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: 08/15/2024] [Revised: 12/10/2024] [Accepted: 12/21/2024] [Indexed: 12/31/2024]
Abstract
Chemobrain can be defined as the development of cognitive side effects following chemotherapy, which is increasingly reported in cancer survivor patients. Chemobrain leads to reduced patients' quality of life by causing different symptoms ranging from strokes and seizures to memory loss and mood disorders. Metformin, an antidiabetic drug, has been proposed as a potential treatment to improve the symptoms of chemotherapy-induced cognitive dysfunction. Several benefits of metformin on chemobrain have been suggested, including anti-inflammation, anti-oxidative stress, restoring impaired mitochondrial function, stabilizing apoptosis, ameliorating impairments to dendritic spine density, normalizing brain senescence protein levels, and attenuating reductions in cell viability, along with reversing learning and memory deficits. These benefits occur through various pathways of metformin, including adenosine monophosphate-activated protein kinase (AMPK), TAp73, and phosphatidylinositol 3-kinase/protein kinase B (Akt) pathways. In addition, metformin can exert neuroprotective effects and restore deficits in brain homeostasis caused by chemotherapy. Furthermore, activation of AMPK following metformin therapy promotes autophagy, stimulates energy production, and improves cell survival. Metformin's interaction with Tap73 and Akt pathways allows for regulated cell proliferation in adult neural precursor cells and cell growth, respectively. Although the negative effects on cerebral function induced by chemotherapeutics have been alleviated by metformin in several instances, further studies are required to confirm its beneficial effects. This research is essential as it addresses the pressing issue of chemobrain, which is on the rise alongside global increases in cancer. Exploring metformin's potential as a neuroprotective agent offers a promising avenue for mitigating these cognitive impairments and highlights the need for further studies to validate its therapeutic mechanisms. This review comprehensively summarises evidence from both in vitro and in vivo studies to demonstrate metformin's effects on cognitive function when co-administered with chemotherapy and identifies gaps in knowledge for further investigation.
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Affiliation(s)
- Evelyn Leddy
- School of Biological Sciences, The University of Manchester, Greater Manchester M13 9PL, United Kingdom; Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Tanawat Attachaipanich
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
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3
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Ligorio F, Vingiani A, Torelli T, Sposetti C, Drufuca L, Iannelli F, Zanenga L, Depretto C, Folli S, Scaperrotta G, Capri G, Bianchi GV, Ferraris C, Martelli G, Maugeri I, Provenzano L, Nichetti F, Agnelli L, Lobefaro R, Fucà G, Fotia G, Mariani L, Morelli D, Ladisa V, De Santis MC, Lozza L, Trecate G, Belfiore A, Brich S, Bertolotti A, Lorenzini D, Ficchì A, Martinetti A, Sottotetti E, Arata A, Corsetto P, Sorrentino L, Rediti M, Salvadori G, Minucci S, Foiani M, Apolone G, Pagani M, Pruneri G, de Braud F, Vernieri C. Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients. Cell Metab 2025; 37:330-344.e7. [PMID: 39694040 DOI: 10.1016/j.cmet.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/04/2024] [Accepted: 11/08/2024] [Indexed: 12/20/2024]
Abstract
In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).
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Affiliation(s)
- Francesca Ligorio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Andrea Vingiani
- Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy; Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Tommaso Torelli
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Caterina Sposetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy
| | - Lorenzo Drufuca
- IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Fabio Iannelli
- Haematopathogy Division, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Lucrezia Zanenga
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Catherine Depretto
- Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Secondo Folli
- Surgical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Gianfranco Scaperrotta
- Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Giuseppe Capri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Giulia V Bianchi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Cristina Ferraris
- Surgical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Gabriele Martelli
- Surgical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Ilaria Maugeri
- Surgical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Leonardo Provenzano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy
| | - Federico Nichetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Luca Agnelli
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Riccardo Lobefaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Giovanni Fucà
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Giuseppe Fotia
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Luigi Mariani
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Daniele Morelli
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Vito Ladisa
- Hospital Pharmacy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Maria Carmen De Santis
- Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Laura Lozza
- Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Giovanna Trecate
- Department of Radiology and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Antonino Belfiore
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Silvia Brich
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Alessia Bertolotti
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Daniele Lorenzini
- Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy; Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Angela Ficchì
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Antonia Martinetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Elisa Sottotetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Alessio Arata
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Paola Corsetto
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Luca Sorrentino
- Surgical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Mattia Rediti
- IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Giulia Salvadori
- IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Saverio Minucci
- Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Marco Foiani
- IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy
| | - Giovanni Apolone
- Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Massimiliano Pagani
- IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Giancarlo Pruneri
- Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy; Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; Oncology and Hematology-Oncology Department, University of Milan, Via Festa del Perdono 7, 20122 Milano, Italy
| | - Claudio Vernieri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; IFOM ETS, the AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
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4
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Wu X, Adame-Garcia SR, Koshizuka K, Vo PTT, Hoang TS, Sato K, Izumi H, Goto Y, Allevato MM, Wood KC, Lippman SM, Gutkind JS. Oncogenic HRAS Induces Metformin Resistance in Head and Neck Cancer by Promoting Glycolytic Metabolism. Cancer Prev Res (Phila) 2024; 17:571-583. [PMID: 39463147 PMCID: PMC11969736 DOI: 10.1158/1940-6207.capr-24-0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 09/19/2024] [Accepted: 10/24/2024] [Indexed: 10/29/2024]
Abstract
Metformin administration has recently emerged as a candidate strategy for the prevention of head and neck squamous cell carcinoma (HNSCC). However, the intricate relationship between genetic alterations in HNSCC and metformin sensitivity is still poorly understood, which prevents the stratification of patients, harboring oral premalignant lesions that may benefit from the chemopreventive activity of metformin. In this study, we investigate the impact of prevalent mutations in HNSCC on response to metformin. Notably, we found that the expression of oncogenic HRAS mutants confers resistance to metformin in isogenic HNSCC cell systems, and that HNSCC cells harboring endogenous HRAS mutations display limited sensitivity to metformin. Remarkably, we found that metformin fails to reduce activation of the mTOR pathway in HRAS oncogene-expressing HNSCC cells in vitro and in vivo, correlating with reduced tumor suppressive activity. Mechanistically, we found that this process depends on the ability of HRAS to enhance glycolytic metabolism, thereby suppressing the requirement for oxidative phosphorylation to maintain the cellular energetic balance. Overall, our study revealed that HNSCC cells with oncogenic HRAS mutations exhibit diminished metformin sensitivity, thus shedding light on a potential mechanism of treatment resistance. This finding may also help explain the limited clinical responses to metformin in cancers with RAS mutations. Ultimately, our study underscores the importance of understanding the impact of the genetic landscape in tailoring precision cancer-preventive approaches in the context of HNSCC and other cancers that are characterized by the presence of a defined premalignant state, and therefore, are amenable to cancer interception strategies. Prevention Relevance: Our findings highlight the challenges of using metformin for cancer prevention in RAS-mutant cancers, where elevated glycolysis may reduce drug efficacy. This underscores the need to explore metformin's potential in early, premalignant stages, before metabolic shifts render it less effective.
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Affiliation(s)
- Xingyu Wu
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Sendi Rafael Adame-Garcia
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Keiichi Koshizuka
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Pham Thuy Tien Vo
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Thomas S. Hoang
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Kuniaki Sato
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Hiroki Izumi
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Yusuke Goto
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Michael M. Allevato
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Kris C. Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Scott M. Lippman
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - J. Silvio Gutkind
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
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5
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Kraj L, Chmiel P, Śliwczyński A, Szymański Ł, Woźniak K, Słodkowski M, Stokłosa T, Wyrwicz L. Synergistic effects of calcium channel blockers and renin-angiotensin inhibitors with gemcitabine-based chemotherapy on the survival of patients with pancreatic cancer. J Cancer Res Clin Oncol 2024; 150:434. [PMID: 39340700 PMCID: PMC11438632 DOI: 10.1007/s00432-024-05962-5] [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: 08/24/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024]
Abstract
PURPOSE Pancreatic cancer remains a significant public health challenge, with poor long-term outcomes due to the lack of effective treatment options. Repurposing commonly used clinical drugs, such as ACE inhibitors, ARBs, CCBs, and metformin, may enhance the efficacy of chemotherapy and offer a promising therapeutic strategy for improving patient outcomes. METHODS A retrospective analysis of concomitant treatment with ACE-Is, ARBs, CCBs, and metformin alongside gemcitabine chemotherapy in patients with pancreatic cancer was conducted. Treatment responses were evaluated, with overall survival (OS) estimated using the Kaplan-Meier method. Additionally, the Cox proportional hazards model was employed to assess the impact of these specific agents on patient survival. RESULTS 4628 patients with various stages of pancreatic cancer were identified in the database between 2007 and 2016. The estimated overall survival (OS) in the analyzed group was 6.9 months (95% CI 6.4-7). The use of any of the analyzed drugs was associated with a significant improvement in mOS of 7.5 months (95% CI 6.8-7.8) vs. 6.7 months (95% CI 6.4-7.0) for patients who did not have additional treatment (p < 0.0001). ARBs, ACE-Is, CCBs, and metformin varied in their effectiveness in prolonging mOS among patients. The longest mOS of 8.9 months (95% CI 7.7-11.6) was observed in patients receiving additional therapy with ARBs, while the shortest mOS of 7.7 months (95% CI 6.5-8.9) was achieved by patients receiving metformin. In the adjusted Cox analysis, metformin was associated with a significantly weaker effect on mOS (p = 0.029). A particularly interesting trend in prolonging 5-year survival was demonstrated by ARBs and CCBs with 14.1% (95% CI 9-22%) and 14.8% (95% CI 11.1-19.6%), respectively, compared to patients not taking these drugs, who achieved a 5-year OS of 3.8% (95% CI 3.2-4.4%). CONCLUSION Our results demonstrate a significant positive impact of ARBs, ACE inhibitors, and CCBs on survival in patients with pancreatic cancer treated with gemcitabine. The addition of these inexpensive and relatively safe drugs in patients with additional comorbidities may represent a potential therapeutic option in this indication. However, prospective clinical trials to evaluate the optimal patient population and further studies to determine the potential impact of these agents on chemotherapy are necessary.
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Affiliation(s)
- Leszek Kraj
- Department of Oncology, Medical University of Warsaw, 02-091, Warsaw, Poland.
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552, Garbatka, Poland.
| | - Paulina Chmiel
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552, Garbatka, Poland
| | - Andrzej Śliwczyński
- National Medical Institute of the Ministry of Interior and Administration, Warsaw, Poland
| | - Łukasz Szymański
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552, Garbatka, Poland
| | - Krzysztof Woźniak
- Department of Oncology, Medical University of Warsaw, 02-091, Warsaw, Poland
| | - Maciej Słodkowski
- Department of General, Gastroenterological and Oncological Surgery, Medical University of Warsaw, 02097, Warsaw, Poland
| | - Tomasz Stokłosa
- Department of Tumor Biology, Genetics Medical University of Warsaw, Warsaw, Poland
| | - Lucjan Wyrwicz
- Department of Oncology, Radiotherapy Maria Sklodowska-Curie National Cancer Research Institute, Warsaw, Poland
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6
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Zhang Z, Zhao M, Wang Q, Wang X, Wang Y, Ge Y, Wu Z, Wang W, Shan L. Forkhead box protein FOXK1 disrupts the circadian rhythm to promote breast tumorigenesis in response to insulin resistance. Cancer Lett 2024; 599:217147. [PMID: 39094826 DOI: 10.1016/j.canlet.2024.217147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/09/2024] [Accepted: 07/27/2024] [Indexed: 08/04/2024]
Abstract
The dysregulation of circadian rhythm oscillation is a prominent feature of various solid tumors. Thus, clarifying the molecular mechanisms that maintain the circadian clock is important. In the present study, we revealed that the transcription factor forkhead box FOXK1 functions as an oncogene in breast cancer. We showed that FOXK1 recruits multiple transcription corepressor complexes, including NCoR/SMRT, SIN3A, NuRD, and REST/CoREST. Among them, the FOXK1/NCoR/SIN3A complex transcriptionally regulates a cohort of genes, including CLOCK, PER2, and CRY2, that are critically involved in the circadian rhythm. The complex promoted the proliferation of breast cancer cells by disturbing the circadian rhythm oscillation. Notably, the nuclear expression of FOXK1 was positively correlated with tumor grade. Insulin resistance gradually became more severe with tumor progression and was accompanied by the increased expression of OGT, which caused the nuclear translocation and increased expression of FOXK1. Additionally, we found that metformin downregulates FOXK1 and exports it from the nucleus, while HDAC inhibitors (HDACi) inhibit the FOXK1-related enzymatic activity. Combined treatment enhanced the expression of circadian clock genes through the regulation of FOXK1, thereby exerting an antitumor effect, indicating that highly nuclear FOXK1-expressing breast cancers are potential candidates for the combined application of metformin and HDACi.
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Affiliation(s)
- Zhaohan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Minghui Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Qian Wang
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute, and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Xilin Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yu Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yuze Ge
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Zicheng Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wenjuan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Lin Shan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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7
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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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8
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van Eijck CWF, Vadgama D, van Eijck CHJ, Wilmink JW. Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study. J Natl Cancer Inst 2024; 116:1374-1383. [PMID: 38530777 PMCID: PMC11308183 DOI: 10.1093/jnci/djae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/12/2024] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors. METHODS We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens. RESULTS Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001). CONCLUSION This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].
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Affiliation(s)
- Casper W F van Eijck
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, the Netherlands
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Disha Vadgama
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Casper H J van Eijck
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam University Medical Centre, Amsterdam, the Netherlands
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9
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Rajagopalan A, Aroori S, Russell TB, Labib PL, Ausania F, Pando E, Roberts KJ, Kausar A, Mavroeidis VK, Marangoni G, Thomasset SC, Frampton AE, Lykoudis P, Maglione M, Alhaboob N, Bari H, Smith AM, Spalding D, Srinivasan P, Davidson BR, Bhogal RH, Dominguez I, Thakkar R, Gomez D, Silva MA, Lapolla P, Mingoli A, Porcu A, Shah NS, Hamady ZZR, Al-Sarrieh B, Serrablo A, Croagh D. Five-year recurrence/survival after pancreatoduodenectomy for pancreatic adenocarcinoma: does pre-existing diabetes matter? Results from the Recurrence After Whipple's (RAW) study. HPB (Oxford) 2024; 26:981-989. [PMID: 38755085 DOI: 10.1016/j.hpb.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 03/27/2024] [Accepted: 04/19/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND Diabetes mellitus (DM) has a complex relationship with pancreatic cancer. This study examines the impact of preoperative DM, both recent-onset and pre-existing, on long-term outcomes following pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). METHODS Data were extracted from the Recurrence After Whipple's (RAW) study, a multi-centre cohort of PD for pancreatic head malignancy (2012-2015). Recurrence and five-year survival rates of patients with DM were compared to those without, and subgroup analysis performed to compare patients with recent-onset DM (less than one year) to patients with established DM. RESULTS Out of 758 patients included, 187 (24.7%) had DM, of whom, 47 of the 187 (25.1%) had recent-onset DM. There was no difference in the rate of postoperative pancreatic fistula (DM: 5.9% vs no DM 9.8%; p = 0.11), five-year survival (DM: 24.1% vs no DM: 22.9%; p = 0.77) or five-year recurrence (DM: 71.7% vs no DM: 67.4%; p = 0.32). There was also no difference between patients with recent-onset DM and patients with established DM in postoperative outcomes, recurrence, or survival. CONCLUSION We found no difference in five-year recurrence and survival between diabetic patients and those without diabetes. Patients with pre-existing DM should be evaluated for PD on a comparable basis to non-diabetic patients.
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Affiliation(s)
| | | | | | - Peter L Labib
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | | | | | - Keith J Roberts
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | | | | | | | | | | | | | | | - Hassaan Bari
- Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan
| | | | | | | | | | | | - Ismael Dominguez
- Salvador Zubiran National Institute of Health Sciences and Nutrition, Mexico City, Mexico
| | - Rohan Thakkar
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Dhanny Gomez
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Michael A Silva
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Andrea Mingoli
- Policlinico Umberto I University Hospital Sapienza, Rome, Italy
| | - Alberto Porcu
- Azienda Ospedaliero Universitaria di Sassari, Sassari, Italy
| | - Nehal S Shah
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Zaed Z R Hamady
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
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10
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De-Leon-Covarrubias UE, Perez-Trujillo JJ, Villa-Cedillo SA, Martinez-Perez AG, Montes-de-Oca-Saucedo CR, Loera-Arias MDJ, Garcia-Garcia A, Saucedo-Cardenas O, Montes-de-Oca-Luna R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites 2024; 14:418. [PMID: 39195514 DOI: 10.3390/metabo14080418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/29/2024] Open
Abstract
Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.
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Affiliation(s)
| | - Jose Juan Perez-Trujillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Sheila Adela Villa-Cedillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | | | | | - Maria de Jesus Loera-Arias
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Aracely Garcia-Garcia
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Odila Saucedo-Cardenas
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Roberto Montes-de-Oca-Luna
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
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11
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Pujalte‐Martin M, Belaïd A, Bost S, Kahi M, Peraldi P, Rouleau M, Mazure NM, Bost F. Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759. Mol Oncol 2024; 18:1719-1738. [PMID: 38214418 PMCID: PMC11223609 DOI: 10.1002/1878-0261.13583] [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: 08/16/2023] [Revised: 11/15/2023] [Accepted: 12/29/2023] [Indexed: 01/13/2024] Open
Abstract
Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.
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Affiliation(s)
- Marc Pujalte‐Martin
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Amine Belaïd
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Simon Bost
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Michel Kahi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Pascal Peraldi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Matthieu Rouleau
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
- CNRS UMR7370, LP2MNiceFrance
| | - Nathalie M. Mazure
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Frédéric Bost
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
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12
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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13
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Benjamin DJ, Haslam A, Prasad V. Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta-analysis of randomized trials. Cancer Med 2024; 13:e7049. [PMID: 38491813 PMCID: PMC10943275 DOI: 10.1002/cam4.7049] [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: 07/15/2023] [Revised: 01/09/2024] [Accepted: 02/08/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS We performed a systematic literature review using PubMed and Web of Science with search terms including "aspirin," "NSAID," "statin" (including specific statin drug names), "metformin," "ACE inhibitors," and "ARBs" (including specific anti-hypertensive drug names) in combination with "cancer." Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.
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Affiliation(s)
| | - Alyson Haslam
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
| | - Vinay Prasad
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
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14
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Elebo N, Abdel-Shafy EA, Cacciatore S, Nweke EE. Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs. Front Genet 2023; 14:1170571. [PMID: 37790705 PMCID: PMC10544984 DOI: 10.3389/fgene.2023.1170571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 08/29/2023] [Indexed: 10/05/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a very lethal disease that typically presents at an advanced stage and is non-compliant with most treatments. Recent technologies have helped delineate associated molecular subtypes and genetic variations yielding important insights into the pathophysiology of this disease and having implications for the identification of new therapeutic targets. Drug repurposing has been evaluated as a new paradigm in oncology to accelerate the application of approved or failed target-specific molecules for the treatment of cancer patients. This review focuses on the impact of molecular subtypes on key genomic alterations in PDAC, and the progress made thus far. Importantly, these alterations are discussed in light of the potential role of drug repurposing in PDAC.
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Affiliation(s)
- Nnenna Elebo
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, Gauteng, South Africa
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
| | - Ebtesam A. Abdel-Shafy
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
- National Research Centre, Cairo, Egypt
| | - Stefano Cacciatore
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
| | - Ekene Emmanuel Nweke
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, Gauteng, South Africa
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15
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Pîrvu EE, Severin E, Pătru RI, Niță I, Toma SA, Macarie RR, Cocioabă CE, Florescu I, Coniac S. Correlations between Demographic, Clinical, and Paraclinical Variables and Outcomes in Patients with KRAS-Mutant or KRAS Wild-Type Metastatic Colorectal Cancer-A Retrospective Study from a Tertiary-Level Center in Romania. Diagnostics (Basel) 2023; 13:2930. [PMID: 37761297 PMCID: PMC10528401 DOI: 10.3390/diagnostics13182930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/16/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is a significant global public health concern and its characteristics in Eastern Europe are underexplored. In this retrospective study, data of 225 patients with metastatic colorectal cancer (mCRC) from the Colțea Clinical Hospital's Oncology Department in Bucharest were analyzed between 2015 and 2023. They were divided into two groups based on the presence of KRAS mutation. The primary objective of the study was to investigate whether the presence of KRAS mutations influenced the prognosis of mCRC and to identify any demographic, clinical, or paraclinical factors associated with KRAS mutations in stage IV CRC. The overall survival for the entire study population was 29 months. There was a trend towards increased survival in the KRAS wild-type group (31 months) compared to the KRAS-mutant group (26 months), but this difference did not reach statistical significance. We found that lower levels of education, advanced T stage, advanced N stage, and M1 stage at diagnosis negatively impacted prognosis. Real-world data are crucial in shaping public policy strategies to better support patients with metastatic CRC. Understanding the correlations between the demographic, clinical, and paraclinical variables and the outcomes in mCRC patients with KRAS-mutant and KRAS wild-type colorectal cancer is essential for improving patient care and treatment strategies in Romania and beyond.
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Affiliation(s)
- Edvina Elena Pîrvu
- Department of Genetics, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | - Emilia Severin
- Department of Genetics, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Raluca Ileana Pătru
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | - Irina Niță
- Department of Medical Oncology, Medicover Hospital, 020331 Bucharest, Romania
| | - Stefania Andreea Toma
- Department of Medical Oncology, Ponderas Academic Hospital, 014142 Bucharest, Romania
| | - Roxana Rodica Macarie
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | | | - Ioana Florescu
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | - Simona Coniac
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
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16
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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17
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Tavares-Valente D, Cannone S, Greco MR, Carvalho TMA, Baltazar F, Queirós O, Agrimi G, Reshkin SJ, Cardone RA. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers (Basel) 2023; 15:3868. [PMID: 37568684 PMCID: PMC10417137 DOI: 10.3390/cancers15153868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
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Affiliation(s)
- Diana Tavares-Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Tiago Miguel Amaral Carvalho
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Gennaro Agrimi
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
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18
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Goodarzi MO, Petrov MS. Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management. Drugs 2023:10.1007/s40265-023-01913-5. [PMID: 37410209 PMCID: PMC10361873 DOI: 10.1007/s40265-023-01913-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.
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Affiliation(s)
- Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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19
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Wang G, Gao H, Dai S, Gao Y, Yin L, Li M, Zhang K, Zhang J, Jiang K, Miao Y, Lu Z. Metformin inhibits neutrophil extracellular traps-promoted pancreatic carcinogenesis in obese mice. Cancer Lett 2023; 562:216155. [PMID: 37030634 DOI: 10.1016/j.canlet.2023.216155] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/10/2023]
Abstract
Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-KrasG12D+/- (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1+ neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression.
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Affiliation(s)
- Guangfu Wang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Hao Gao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Shangnan Dai
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Yong Gao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Lingdi Yin
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Mingna Li
- Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Kai Zhang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Jingjing Zhang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Kuirong Jiang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China; Pancreas Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, China.
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Pancreas Institute, Nanjing Medical University, Nanjing, 210000, China.
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20
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Lord SR, Harris AL. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic? Br J Cancer 2023; 128:958-966. [PMID: 36823364 PMCID: PMC10006178 DOI: 10.1038/s41416-023-02204-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Over the past 15 years, there has been great interest in the potential to repurpose the diabetes drug, metformin, as a cancer treatment. However, despite considerable efforts being made to investigate its efficacy in a number of large randomised clinical trials in different tumour types, results have been disappointing to date. This perspective article summarises how interest initially developed in the oncological potential of metformin and the diverse clinical programme of work to date including our contribution to establishing the intra-tumoral pharmacodynamic effects of metformin in the clinic. We also discuss the lessons that can be learnt from this experience and whether a further clinical investigation of metformin in cancer is warranted.
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Affiliation(s)
- Simon R Lord
- Department of Oncology, University of Oxford, Oxford, UK.
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21
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Patel PJ, Shah JS. Metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer. ANNALES PHARMACEUTIQUES FRANÇAISES 2023:S0003-4509(23)00023-8. [PMID: 36907329 DOI: 10.1016/j.pharma.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 01/17/2023] [Accepted: 03/07/2023] [Indexed: 03/13/2023]
Abstract
OBJECTIVES The present study aimed to evaluate the effect of metformin pretreatment on the potentiation of antiproliferative action of doxorubicin against breast cancer. MATERIAL AND METHODS Female Wistar rats were administered with 7,12-Dimethylbenz(a)anthracene (DMBA) (35mg) in 1mL olive oil subcutaneously beneath the mammary gland. Animals were pretreated with metformin (Met) 200mg/kg two weeks before DMBA administration. DMBA control groups received doxorubicin (Dox) (4mg/kg and 2mg/kg), Met (200mg/kg) alone and in combination with Dox (4mg/kg). Met pre-treated DMBA control groups received Dox 4mg/kg and 2mg/kg. RESULTS Met pre-treated groups treated with Dox exhibited a decrease in tumor incidence, tumor volume and increased survival rate than the DMBA group. Organ-to-body weight ratios and histopathology of heart, liver and lungs of Met pre-treated groups treated with Dox showed lesser toxicity than Dox treated DMBA control groups. There was a noteworthy decrease in malondialdehyde levels and a substantial increase in the levels of reduced glutathione together with a significant decrease in the levels of inflammatory markers like IL-6, IL-1β and NF-κB in Met pre-treated groups treated with Dox. Histopathology of breast tumors revealed better control of tumors in Met pre-treated groups treated with Dox than DMBA control group. Immunohistochemistry and real-time PCR data revealed a significant reduction in Ki67 expression in Met pre-treated groups treated with Dox as compared to the DMBA control group. CONCLUSION The present study suggests that metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer.
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Affiliation(s)
- P J Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, 382481, India.
| | - J S Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, 382481, India.
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22
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Nowicka Z, Matyjek A, Płoszka K, Łaszczych M, Fendler W. Metanalyses on metformin's role in pancreatic cancer suffer from severe bias and low data quality - An umbrella review. Pancreatology 2023; 23:192-200. [PMID: 36697348 DOI: 10.1016/j.pan.2023.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/11/2023] [Accepted: 01/15/2023] [Indexed: 01/27/2023]
Abstract
AIMS Discrepancies in the preclinical evidence, retrospective studies, and randomized trials evaluating metformin's role in pancreatic cancer are difficult to disentangle. We aimed to critically and systematically examine the quality and sources of heterogeneity between meta-analyses investigating the association between metformin intake and the prognosis of patients with pancreatic cancer. MATERIALS AND METHODS We performed a literature search on PubMed, MEDLINE, Embase, and Scopus on October 31, 2021 to identify meta-analyses investigating the impact of metformin treatment on the prognosis of patients with pancreatic cancer. Meta-analyses quality was assessed using according to the AMSTAR 2 criteria. We assessed bias in individual studies included in the meta-analyses, with particular attention to immortal time bias and quality of reporting. RESULTS Eleven meta-analyses describing 24 individual studies were included. All meta-analyses were rated low (n = 5) or critically low (n = 6) quality. Only 4 followed PRISMA reporting guidelines and only in 5 presented data were sufficient to replicate the analyses. Most meta-analyses combined results from clinical trials and retrospective studies (n = 6); patients with different cancer stages (resectable vs advanced) and from studies with different control group definitions. Immortal time bias was present and not accounted for in most (65.2%) of the individual retrospective studies; almost all (n = 9) meta-analyses failed to identify and correct for this source of bias. CONCLUSIONS Meta-analyses describing the association of metformin use in patients with pancreatic cancer are plagued by various types of bias inherent in retrospective studies. The quality of evidence linking metformin to decreased pancreatic cancer mortality is generally low.
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Affiliation(s)
- Zuzanna Nowicka
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Anna Matyjek
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland; Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 04-141, Warsaw, Poland
| | - Katarzyna Płoszka
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Mateusz Łaszczych
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
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23
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Van J, Hahn Y, Silverstein B, Li C, Cai F, Wei J, Katiki L, Mehta P, Livatova K, DelPozzo J, Kobayashi T, Huang Y, Kobayashi S, Liang Q. Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death. INTERNATIONAL JOURNAL OF DRUG DISCOVERY AND PHARMACOLOGY 2023; 2:37-51. [PMID: 38487671 PMCID: PMC10939033 DOI: 10.53941/ijddp.0201004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.
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Affiliation(s)
- Jennifer Van
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Younghee Hahn
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Brett Silverstein
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Cairong Li
- Clinical Medical College, Hubei University of Science and Technology, Xianning 332306, China
| | - Fei Cai
- Clinical Medical College, Hubei University of Science and Technology, Xianning 332306, China
| | - Jia Wei
- Department of Cardiology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710000, China
| | - Lokesh Katiki
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Puja Mehta
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Katherine Livatova
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Jaclyn DelPozzo
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Tamayo Kobayashi
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Yuan Huang
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Satoru Kobayashi
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Qiangrong Liang
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
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24
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Antitumor Therapy Targeting the Tumor Microenvironment. JOURNAL OF ONCOLOGY 2023; 2023:6886135. [PMID: 36908706 PMCID: PMC10005879 DOI: 10.1155/2023/6886135] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/13/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023]
Abstract
The development and progression of tumors in human tissues extensively rely on its surrounding environment, that is, tumor microenvironment which includes a variety of cells, molecules, and blood vessels. These components are modified, organized, and integrated to support and facilitate the growth, invasion, and metabolism of tumor cells, suggesting them as potential therapeutic targets in anticancer treatment. An increasing number of pharmacological agents have been developed and clinically applied to target the oncogenic components in the tumor microenvironment, and in this review, we will summarize these pharmacological agents that directly or indirectly target the cellular or molecular components in the tumor microenvironment. However, difficulties and challenges still exist in this field, which will also be reported in this literature.
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25
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Chen Y, Qian FJ, Ye ZQ, Xie WX, He YD, Huang JR, Tian L, Gu DN. Anticancer Benefit of Metformin in Patients With Early-Stage Pancreatic Cancer: A Retrospective Cohort Study. Technol Cancer Res Treat 2022; 21:15330338221138208. [PMID: 36583563 PMCID: PMC9806383 DOI: 10.1177/15330338221138208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background: Epidemiologic studies have produced conflicting results on the effects of metformin on pancreatic cancer. This study aimed to observe and analyze whether metformin use is associated with better prognosis in pancreatic cancer. Materials and Methods: In this retrospective cohort study, all baseline data were retrieved from The Chinese Medicine Information Retrieval System (https://dc.wzhospital.cn/vpn/index.html) of The First Affiliated Hospital of Wenzhou Medical University. Survival data were collected by follow-up visits and medical records. Overall survival was the primary endpoint, while progression-free survival and disease-free survival were secondary endpoints. Progression or recurrence was assessed with radiologic images. Results: Seventy-six metformin users and 92 metformin nonusers diagnosed with pancreatic cancer from 2012 to 2020 in this hospital were enrolled. The adjusted hazard ratio for overall survival for metformin users was 0.50 (95% confidence interval = 0.33-0.76), where median overall survival was 16.0 months for metformin users versus 11.5 months for metformin nonusers. The protective effect was also found by analyzing progression-free survival (adjusted hazard ratio = 0.39, 95% confidence interval = 0.18-0.86) and disease-free survival (adjusted hazard ratio = 0.30, 95% confidence interval = 0.14-0.68). In the subgroup analysis, metformin use had a statistically significant association with prolongation of survival in stage I to II pancreatic cancer patients (hazard ratio = 0.47, 95% confidence interval = 0.25-0.91), but not for advanced tumor stage (hazard ratio for IV stage = 0.62, 95% confidence interval = 0.33-1.19), after adjustment for other risk factors. Conclusion: Metformin use is related to favorable survival outcomes of pancreatic cancer, especially in early tumor stage.
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Affiliation(s)
- Yang Chen
- Wenzhou Medical University, Wenzhou, China
| | | | - Zhi-qiang Ye
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | | | - You-di He
- Wenzhou Medical University, Wenzhou, China
| | | | - Ling Tian
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Ling Tian, Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Dian-na Gu, Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Dian-na Gu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells. Cancers (Basel) 2022; 14:cancers14225597. [PMID: 36428689 PMCID: PMC9688551 DOI: 10.3390/cancers14225597] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.
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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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Ji H, Zhang Q, Wang XX, Li J, Wang X, Pan W, Zhang Z, Ma B, Zhang HM. Identification of stromal microenvironment characteristics and key molecular mining in pancreatic cancer. Discov Oncol 2022; 13:83. [PMID: 36006549 PMCID: PMC9411435 DOI: 10.1007/s12672-022-00532-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/07/2022] [Indexed: 11/07/2022] Open
Abstract
PURPOSE Pancreatic cancer is one of the deadliest cancers worldwide. The extracellular matrix (ECM) microenvironment affects the drug sensitivity and prognosis of pancreatic cancer patients. This study constructed an 8-genes pancreatic ECM scoring (PECMS) model, to classify the ECM features of pancreatic cancer, analyze the impact of ECM features on survival and drug sensitivity, and mine key molecules that influence ECM features in pancreatic cancer. METHODS GSVA score calculation and clustering were performed in TCGA-PAAD patients. Lasso regression was used to construct the PECMS model. The association between PECMS and patient survival was analyzed and validated in the CPTAC-3 dataset of TCGA and our single-center retrospective cohort. The relationships between PECMS and features of the matrix microenvironment were analyzed. Finally, PECMS feature genes were screened and verified in pancreatic cancer specimens to select key genes associated with the ECM microenvironment. RESULT The survival of the PECMS-high group was significantly worse. The PECMS-high group showed higher oxidative stress levels, lower levels of antigen presentation- and MHC-I molecule-related pathways, and less immune effector cell infiltration. Data from IMvigor-210 cohort suggested that PECMS-low group patients were more sensitive to immune checkpoint blockers. The PECMS score was negatively correlated with chemotherapy drug sensitivity. The negative association of PECMS with survival and drug sensitivity was validated in our retrospective cohort. KLHL32 expression predicted lower oxidative stress level and more immune cells infiltrate in pancreatic cancer. CONCLUSION PECMS is an effective predictor of prognosis and drug sensitivity in pancreatic cancer patients. KLHL32 may play an important role in the construction of ECM, and the mechanism is worth further study.
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Affiliation(s)
- Hongchen Ji
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China
- Faculty of Hepatopancreatobiliary Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, China
| | - Qiong Zhang
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China
| | - Xiang-Xu Wang
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China
| | - Junjie Li
- Department of Emergency, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, China
| | - Xiaowen Wang
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China
| | - Wei Pan
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China
| | - Zhuochao Zhang
- Faculty of Hepatopancreatobiliary Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, China
| | - Ben Ma
- Faculty of Hepatopancreatobiliary Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, China
| | - Hong-Mei Zhang
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, China.
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Di Magno L, Di Pastena F, Bordone R, Coni S, Canettieri G. The Mechanism of Action of Biguanides: New Answers to a Complex Question. Cancers (Basel) 2022; 14:cancers14133220. [PMID: 35804992 PMCID: PMC9265089 DOI: 10.3390/cancers14133220] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 01/27/2023] Open
Abstract
Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.
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Affiliation(s)
- Laura Di Magno
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Fiorella Di Pastena
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Rosa Bordone
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Sonia Coni
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.D.M.); (F.D.P.); (R.B.); (S.C.)
- Istituto Pasteur—Fondazione Cenci—Bolognetti, 00161 Rome, Italy
- Correspondence:
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Ma M, Li W, Xu L, Ping F, Zhang H, Li Y. Diabetes duration and weight loss are associated with onset age and remote metastasis of pancreatic cancer in patients with diabetes mellitus. J Diabetes 2022; 14:261-270. [PMID: 35167190 PMCID: PMC9060030 DOI: 10.1111/1753-0407.13259] [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: 08/15/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE To analyze the clinical characteristics of patients with pancreatic cancer (PC) and diabetes and to explore the impact of diabetes duration, weight loss, and hypoglycemic drugs on the tumor biological behavior of PC. METHODS This is a retrospective study on patients with PC and diabetes. Subjects were grouped according to the onset age of PC, distant metastasis, duration of diabetes, degree of weight loss (∆Wt), and type of hypoglycemic drugs. Logistic regression analysis was used to evaluate the association between diabetes duration, weight loss, hypoglycemic drugs, and early-onset PC, distant metastasis. RESULTS Compared with late-onset PC, patients with early-onset PC had a higher proportion of new-onset DM (35 [79.5%] vs. 217 [46.9%], p < 0.001), smoker, drinker, and more obvious weight loss (8.5 [3.8, 15] kg vs. 5 [0, 10] kg, p < 0.001). Patients with remote metastasis had an earlier diagnosis age, heavier weight loss, lower body mass index, and were more likely to be smokers but had cancer less likely to be localized in the head of pancreas. Regression analysis showed that new-onset diabetes and weight loss were independently correlated to early-onset PC: odds ratio (OR) = 3.38 (95% CI 1.36-8.4, p = 0.09; OR = 1.56 (95% CI 1.16-2.1), p = 0.003, respectively. In contrast, long-term diabetes, and heavy weight loss were independently associated with remote metastasis: OR = 3.38 (95% CI 1.36-8.4, p = 0.09; OR = 1.56 (95% CI 1.16-2.1), p = 0.003, respectively. CONCLUSION New-onset diabetes and weight loss were common presentation and risk factors of early-onset PC, which required more attention. Long-term diabetes and heavy weight loss were risk factors contributing to distant metastases, indicating potential risk factors contributing to the adverse prognosis of patients with PC.
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Affiliation(s)
- Minglei Ma
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
- Department of Endocrinology, Beijing Shijitan HospitalCapital Medical UniversityBeijingChina
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of HealthPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
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Gan X, Cao C, He Y, Hu X, Peng X, Su Y. The metformin has no significant anticancer effect on patients with advanced or unresectable cancer: systematic review and meta-analysis. Curr Pharm Des 2022; 28:1351-1358. [PMID: 35352646 DOI: 10.2174/1381612828666220329113434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/14/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND At present, the antitumor effect of metformin is controversial. Previous meta-analyses included observational studies, of which the results can be influenced by many confounders, affecting the result of meta-analyses and weakening the strength of evidence. Therefore, we conducted a meta-analysis to confirm the effect of metformin use on patients with advanced or unresectable cancers, including randomized clinical trials (RCTs). METHODS We searched for RCTs in accordance with the inclusion and exclusion criteria. A meta-analysis was conducted to combine hazard ratios (HRs) or risk ratios (RRs) and their 95% confidence intervals (CIs), using a random-effects model. RESULTS Finally, 7 eligible RCTs were included in meta-analysis. Overall, the combined results revealed that treatment with metformin did not improve the overall survival (OS) of patients (HR, 1.12; 95%CI, 0.91-1.37, P>0.05), and there was no clear evidence that metformin use was related to improved progression-free survival (PFS) (HR,1.17; 95%CI, 0.97-1.40; P>0.05). The pooled RR for grade III or IV adverse events was 0.92 (95%CI, 0.52-1.60; P>0.05), indicating that the use of metformin was not significantly related to increased toxicity. CONCLUSION Metformin does not significantly improve the survival of patients with advanced or unresectable cancer, regardless of cancer type and region. Open Science Framework: DOI 10.17605/OSF.IO/SPKE8.
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Affiliation(s)
- Xinyan Gan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chang Cao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yan He
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaolin Hu
- Department of Nursing, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yonglin Su
- Rehabilitation Medicine Center and Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China;
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Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H. The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:467. [PMID: 35454306 PMCID: PMC9032206 DOI: 10.3390/medicina58040467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022]
Abstract
Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.
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Affiliation(s)
- Aiste Gulla
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
- Center of Visceral Medicine and Translational Research, Department of Surgery, Georgetown University Hospital, 3800 Reservoir Road Northwest BLES Building 1st. Floor, Washington, DC 20007, USA
| | - Urte Andriusaityte
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Gabrielius Tomas Zdanys
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Elena Babonaite
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Kestutis Strupas
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
| | - Helena Kelly
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland;
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Greene J, Segaran A, Lord S. Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications. Semin Cancer Biol 2022; 86:851-859. [PMID: 35122973 DOI: 10.1016/j.semcancer.2022.02.002] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 12/11/2022]
Abstract
Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.
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Affiliation(s)
- John Greene
- Department of Oncology, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Ashvina Segaran
- Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
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Singh M, Nicol AT, DelPozzo J, Wei J, Singh M, Nguyen T, Kobayashi S, Liang Q. Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity. Front Cardiovasc Med 2022; 9:839644. [PMID: 35141304 PMCID: PMC8818847 DOI: 10.3389/fcvm.2022.839644] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by in vivo studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.
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Affiliation(s)
- Manrose Singh
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Akito T. Nicol
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Jaclyn DelPozzo
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Jia Wei
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xian, China
| | - Mandeep Singh
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Tony Nguyen
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Satoru Kobayashi
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Qiangrong Liang
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
- *Correspondence: Qiangrong Liang
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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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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Tortelli TC, Tamura RE, de Souza Junqueira M, da Silva Mororó J, Bustos SO, Natalino RJM, Russell S, Désaubry L, Strauss BE, Chammas R. Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells. Aging (Albany NY) 2021; 13:21914-21940. [PMID: 34528900 PMCID: PMC8507253 DOI: 10.18632/aging.203528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/25/2021] [Indexed: 12/24/2022]
Abstract
Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.
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Affiliation(s)
- Tharcisio Citrangulo Tortelli
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Rodrigo Esaki Tamura
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
- Laboratory of Cancer Molecular Biology, Federal University of São Paulo, São Paulo, SP 04039-002, Brazil
| | - Mara de Souza Junqueira
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Janio da Silva Mororó
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Silvina Odete Bustos
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Renato Jose Mendonça Natalino
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Shonagh Russell
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Laurent Désaubry
- Laboratory of Regenerative Nanomedicine (RNM), INSERM U 1260, University of Strasbourg, CRBS, Strasbourg 67000, France
| | - Bryan Eric Strauss
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
| | - Roger Chammas
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13184612. [PMID: 34572837 PMCID: PMC8468269 DOI: 10.3390/cancers13184612] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.
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Interplay of Immunometabolism and Epithelial-Mesenchymal Transition in the Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms22189878. [PMID: 34576042 PMCID: PMC8466075 DOI: 10.3390/ijms22189878] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 02/07/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) and metabolic reprogramming in cancer cells are the key hallmarks of tumor metastasis. Since the relationship between the two has been well studied, researchers have gained increasing interest in the interplay of cancer cell EMT and immune metabolic changes. Whether the mutual influences between them could provide novel explanations for immune surveillance during metastasis is worth understanding. Here, we review the role of immunometabolism in the regulatory loop between tumor-infiltrating immune cells and EMT. We also discuss the challenges and perspectives of targeting immunometabolism in cancer treatment.
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Diabetes and pancreatic cancer: recent insights with implications for early diagnosis, treatment and prevention. Curr Opin Gastroenterol 2021; 37:539-543. [PMID: 34387256 DOI: 10.1097/mog.0000000000000763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Recent insights into the complex relationship between diabetes and pancreatic cancer have the potential to help direct future approaches to early detection, treatment and prevention. RECENT FINDINGS Insulin resistance and hyperinsulinemia have been identified as factors that relate to risk of pancreatic cancer among patients with long-standing diabetes. In contrast, weight loss in the setting of new-onset diabetes can help identify patients at an increased risk for harbouring pancreatic-cancer related disturbances in glucose metabolism. Insights into the implications of poor glycaemic control in patients undergoing resection for pancreatic cancer have the potential to improve both surgical and oncologic outcomes. Finally, among antidiabetic medications, metformin continues to be evaluated as a potential adjunctive therapeutic agent, although recent evidence supports the safety of incretins with respect to pancreatic cancer. SUMMARY This review highlights recent developments in these areas with an emphasis on opportunities for improved early diagnosis, treatment and prevention in pancreatic cancer.
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Støer NC, Bouche G, Pantziarka P, Sloan EK, Andreassen BK, Botteri E. Use of non-cancer drugs and survival among patients with pancreatic adenocarcinoma: a nationwide registry-based study in Norway. Acta Oncol 2021; 60:1146-1153. [PMID: 34338111 DOI: 10.1080/0284186x.2021.1953136] [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] [Indexed: 12/17/2022]
Abstract
BACKGROUND The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. MATERIAL AND METHODS The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. RESULTS In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. CONCLUSION The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.
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Affiliation(s)
| | | | | | - Erica K. Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Division of Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | | | - Edoardo Botteri
- Department of Research, Cancer Registry of Norway, Oslo, Norway
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway
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Hart PA, Andersen DK, Petrov MS, Goodarzi MO. Distinguishing diabetes secondary to pancreatic diseases from type 2 diabetes mellitus. Curr Opin Gastroenterol 2021; 37:520-525. [PMID: 34265796 PMCID: PMC8364493 DOI: 10.1097/mog.0000000000000754] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Diabetes secondary to pancreatic diseases (i.e., acute pancreatitis, chronic pancreatitis, and pancreatic cancer) is increasingly studied, but remains challenging to distinguish from type 2 diabetes (T2DM). We review the clinical significance and potential biomarkers that may help differentiate these types of diabetes. RECENT FINDINGS Recent studies have identified several complications (including nonvascular) that occur more frequently in patients with diabetes secondary to acute and chronic pancreatitis than T2DM, and biomarkers to differentiate these types of diabetes. There have been advances that may enable the enrichment of a population of adults with new onset diabetes to potentially screen for occult pancreatic cancer, but efforts are needed to identify and validate promising diagnostic biomarkers. SUMMARY High-quality studies are needed to more precisely understand the risk factors and natural course of diabetes secondary to pancreatic diseases. Mechanistic and interventional studies are awaited to provide insights that will distinguish diabetes secondary to pancreatic diseases and refine the management of hyperglycemia in this patient population.
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Affiliation(s)
- Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Maxim S. Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Mark O. Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Dujardin P, Baginska AK, Urban S, Grüner BM. Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC. Cancers (Basel) 2021; 13:4187. [PMID: 34439341 PMCID: PMC8394487 DOI: 10.3390/cancers13164187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 12/14/2022] Open
Abstract
Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.
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Affiliation(s)
- Philip Dujardin
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen at the University Duisburg-Essen, 45147 Essen, Germany
| | - Anna K Baginska
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen at the University Duisburg-Essen, 45147 Essen, Germany
| | - Sebastian Urban
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen at the University Duisburg-Essen, 45147 Essen, Germany
| | - Barbara M Grüner
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen at the University Duisburg-Essen, 45147 Essen, Germany
- German Cancer Consortium (DKTK) Partner Site Essen/Düsseldorf, 45147 Essen, Germany
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Diabetes and pancreatic cancer: Exploring the two-way traffic. World J Gastroenterol 2021; 27:4939-4962. [PMID: 34497428 PMCID: PMC8384733 DOI: 10.3748/wjg.v27.i30.4939] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Gyawali M, Venkatesan N, Ogeyingbo OD, Bhandari R, Botleroo RA, Kareem R, Ahmed R, Elshaikh AO. Magic of a Common Sugar Pill in Cancer: Can Metformin Raise Survival in Pancreatic Cancer Patients? Cureus 2021; 13:e16916. [PMID: 34367843 PMCID: PMC8343553 DOI: 10.7759/cureus.16916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.
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Affiliation(s)
- Mallika Gyawali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nanditha Venkatesan
- Internal Medicine, All India Institute of Medical Sciences, Raipur, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Opemipo D Ogeyingbo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Saint James School of Medicine, Park Ridge, USA.,Public Health, Walden University, Minneapolis, USA
| | - Renu Bhandari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Rinky A Botleroo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roaa Kareem
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Rowan Ahmed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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De Lellis L, Veschi S, Tinari N, Mokini Z, Carradori S, Brocco D, Florio R, Grassadonia A, Cama A. Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates. Cancers (Basel) 2021; 13:3946. [PMID: 34439102 PMCID: PMC8394389 DOI: 10.3390/cancers13163946] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
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Affiliation(s)
- Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Zhirajr Mokini
- European Society of Anaesthesiology and Intensive Care (ESAIC) Mentorship Programme, ESAIC, 24 Rue des Comédiens, BE-1000 Brussels, Belgium;
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Davide Brocco
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Antonino Grassadonia
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
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48
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Chen YH, Huang YC, Yang SF, Yen HH, Tsai HD, Hsieh MC, Hsiao YH. Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:1491-1503. [PMID: 33886150 DOI: 10.1002/tox.23146] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/12/2021] [Accepted: 04/02/2021] [Indexed: 06/12/2023]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 μM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 μM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.
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Affiliation(s)
- Ya-Hui Chen
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ying-Chih Huang
- Department of Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Horng-Der Tsai
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Chia Hsieh
- Intelligent Diabetes Metabolism and Exercise Center, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Hsuan Hsiao
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
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49
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Skinner H, Hu C, Tsakiridis T, Santana-Davila R, Lu B, Erasmus JJ, Doemer AJ, Videtic GMM, Coster J, Yang AX, Lee RY, Werner-Wasik M, Schaner PE, McCormack SE, Esparaz BT, McGarry RC, Bazan J, Struve T, Paulus R, Bradley JD. Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial. JAMA Oncol 2021; 7:1324-1332. [PMID: 34323922 DOI: 10.1001/jamaoncol.2021.2318] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Importance Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, Setting, and Participants The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions Chemoradiation and consolidation chemotherapy with or without metformin. Main Outcomes and Measures The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and Relevance In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial Registration ClinicalTrials.gov Identifier: NCT02186847.
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Affiliation(s)
- Heath Skinner
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Chen Hu
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | | | - Bo Lu
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | | | | | | | | | | | | | | | | | - Steven E McCormack
- Metro-Minnesota Community Oncology Research Consortium, St Louis Park, Minnesota
| | | | | | - Jose Bazan
- Ohio State University Comprehensive Cancer Center, Columbus
| | - Timothy Struve
- University of Cincinnati/Barrett Cancer Center, Cincinnati, Ohio
| | - Rebecca Paulus
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
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50
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Djamgoz MBA, Jentzsch V. Integrative Management of Pancreatic Cancer (PDAC): Emerging Complementary Agents and Modalities. Nutr Cancer 2021; 74:1139-1162. [PMID: 34085871 DOI: 10.1080/01635581.2021.1934043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with "repurposed" aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.
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Affiliation(s)
- Mustafa B A Djamgoz
- Department of Life Sciences, Imperial College London, London, UK
- Biotechnology Research Centre, Cyprus International University, Nicosia, Cyprus
| | - Valerie Jentzsch
- Department of Life Sciences, Imperial College London, London, UK
- Department of Health Policy, London School of Economics and Political Science, London, UK
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