|
1
|
Torres C, Mancinelli G, Chen JWE, Cordoba-Chacon J, Pins D, Saeed S, McKinney R, Castellanos K, Orsi G, Singhal M, Patel A, Acebedo J, Coleman A, Heneche J, Yalagala PCR, Subbaiah PV, Leal C, Grimaldo S, Ortuno FM, Bishehsari F, Grippo PJ. Cell Membrane Fatty Acids and PIPs Modulate the Etiology of Pancreatic Cancer by Regulating AKT. Nutrients 2024; 17:150. [PMID: 39796583 PMCID: PMC11722924 DOI: 10.3390/nu17010150] [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: 10/24/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the worst solid malignancies in regard to outcomes and metabolic dysfunction leading to cachexia. It is alarming that PDAC incidence rates continue to increase and warrant the need for innovative approaches to combat this disease. Due to its relatively slow progression (10-20 years), prevention strategies represent an effective means to improve outcomes. One of the risk factors for many cancers and for pancreatic cancer in particular is diet. Hence, our objective is to understand how a diet rich in ω3 and ω6 polyunsaturated fatty acids affects the progression of this disease. Methods: We investigated polyunsaturated fatty acid (PUFA) effects on disease progression employing both in vitro (PDAC cell lines) and in vivo (EL-Kras and KC mice) approaches. Also, we gathered data from the National Health and Nutrition Examination Survey (NHANES) and the National Cancer Institute (NCI) from 1999 to 2017 for a retrospective observational study. Results: The consumption of PUFAs in a patient population correlates with increased PDAC incidence, particularly when the ω3 intake increases to a lesser extent than ω6. Our data demonstrate dietary PUFAs can be incorporated into plasma membrane lipids affecting PI3K/AKT signaling and support the emergence of membrane-targeted therapies. Moreover, we show that the phospholipid composition of a lipid nanoparticle (LNP) can impact the cell membrane integrity and, ultimately, cell viability after administration of these LNPs. Conclusions: Cancer prevention is impactful particularly for those with very poor prognosis, including pancreatic cancer. Our results point to the importance of dietary intervention in this disease when detected early and the potential to improve the antiproliferative effect of drug efficacy when combined with these regimens in later stages of pancreatic cancer.
Collapse
Affiliation(s)
- Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigacion Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Georgina Mancinelli
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jee-Wei Emily Chen
- Department of Materials Science & Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; (J.-W.E.C.)
| | - Jose Cordoba-Chacon
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Danielle Pins
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Sara Saeed
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Ronald McKinney
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Karla Castellanos
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | | | - Megha Singhal
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Akshar Patel
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jose Acebedo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Adonis Coleman
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jorge Heneche
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Poorna Chandra Rao Yalagala
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Papasani V. Subbaiah
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Cecilia Leal
- Department of Materials Science & Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; (J.-W.E.C.)
| | - Sam Grimaldo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Francisco M. Ortuno
- Department of Computer Architecture and Computer Technology, University of Granada, 18071 Granada, Spain
| | - Faraz Bishehsari
- Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Paul J. Grippo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois Chicago, 840 S. Wood Street, CSB 708, Chicago, IL 60612, USA
| |
Collapse
|
|
2
|
Jiang YL, Li X, Tan YW, Fang YJ, Liu KY, Wang YF, Ma T, Ou QJ, Zhang CX. Docosahexaenoic acid inhibits the invasion and migration of colorectal cancer by reversing EMT through the TGF-β1/Smad signaling pathway. Food Funct 2024; 15:9420-9433. [PMID: 39189524 DOI: 10.1039/d4fo02346c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
The primary cause of mortality in colorectal cancer (CRC) patients is tumor metastasis. The epithelial-mesenchymal transition (EMT) stands out as a crucial factor promoting the metastasis of CRC. Previous findings suggest a potential inhibitory effect of docosahexaenoic acid (DHA) on CRC metastasis, but the precise mechanism remains unknown, this study aims to explore this issue. We assessed metastasis and recurrence, all-cause mortality, and cancer-related mortality rates according to DHA intake in independent CRC cohorts (n = 367) by survival analysis. The ability of DHA to block CRC cell migration and invasion was tested using transwell and wound-healing assays. The regulation of EMT marker genes in CRC by DHA was detected by quantitative real-time PCR (qPCR) and immunoblotting, and the effect of DHA on the TGF-β1/Smad signaling pathway was further investigated. These cellular findings were validated using a subcutaneous CRC mouse model. Survival analyses showed that lower DHA intake was associated with a higher risk of CRC metastasis and a poorer prognosis. In vitro experiments showed that DHA inhibits the TGF-β1/Smad signaling pathway and regulates downstream transcription factors, thereby reversing the EMT and inhibiting invasion and migration. In the mouse model, dietary DHA supplementation effectively increased blood DHA concentrations and inhibited CRC metastasis. Our study demonstrated that DHA inhibits CRC invasion and metastasis by inhibiting the TGF-β1/Smad signaling pathway. Increased intake of DHA among CRC patients may provide additional benefits to the prognosis of colorectal cancer.
Collapse
Affiliation(s)
- Yi-Ling Jiang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Xue Li
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Ya-Wen Tan
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Yu-Jing Fang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Kai-Yan Liu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Yi-Fan Wang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Ting Ma
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Qing-Jian Ou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Cai-Xia Zhang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| |
Collapse
|
|
3
|
Kisioglu B, Tamer F. Impact of lipid emulsions in parenteral nutrition on platelets: a literature review. J Nutr Sci 2024; 13:e18. [PMID: 38572365 PMCID: PMC10988153 DOI: 10.1017/jns.2024.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 04/05/2024] Open
Abstract
Lipid emulsions are essential components of parenteral nutrition solutions that provide energy and essential fatty acids. The complexity of the formulations of lipid emulsions may lead to adverse outcomes such as platelet reactivity and changes in platelet aggregation and related coagulation. Platelets are responsible for haemostasis; they activate and demonstrate morphological changes upon extracellular factors to maintain blood fluidity and vascular integrity. Although parenteral nutrition lipid emulsions are generally found safe with regard to modulation of platelet activity, studies are still accumulating. Thus, this review aims to investigate platelet-related changes by parenteral nutrition lipid emulsions in human studies. Studies have pointed out patients at risk of bleeding and increased platelet aggregation responses due to the administration of lipid emulsions. Lipid emulsions may further benefit patients at high risk of thrombosis due to anti-thrombotic effects and should be cautiously used in patients with thrombocytopenia. The reported platelet-related changes might be associated with the fatty acid change in the plasma membranes of platelets following changes in platelet synthesis and plasma levels of eicosanoids. In conclusion, studies investigating platelets and parenteral nutrition should be supported to minimize the adverse effects and to benefit from the potential protective effects of parenteral nutrition lipid emulsions.
Collapse
Affiliation(s)
- Betul Kisioglu
- Hacettepe University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Ankara, Turkey
- Duzce University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Duzce, Turkey
| | - Funda Tamer
- Hacettepe University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Ankara, Turkey
| |
Collapse
|
|
4
|
Akbar S, Rahman A, Ahmad N, Imran M, Hafeez Z. Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer. Cancer Treat Res 2024; 191:57-93. [PMID: 39133404 DOI: 10.1007/978-3-031-55622-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.
Collapse
Affiliation(s)
- Samina Akbar
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France.
| | - Abdur Rahman
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Nazir Ahmad
- Faculty of Life Sciences, Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Imran
- Department of Biosciences, Faculty of Sciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan
| | - Zeeshan Hafeez
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France
| |
Collapse
|
|
5
|
Theinel MH, Nucci MP, Alves AH, Dias OFM, Mamani JB, Garrigós MM, Oliveira FA, Rego GNA, Valle NME, Cianciarullo G, Gamarra LF. The Effects of Omega-3 Polyunsaturated Fatty Acids on Breast Cancer as a Preventive Measure or as an Adjunct to Conventional Treatments. Nutrients 2023; 15:nu15061310. [PMID: 36986040 PMCID: PMC10052714 DOI: 10.3390/nu15061310] [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: 01/20/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/10/2023] Open
Abstract
In order to understand how omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements affect breast cancer prevention and treatment, a systematic review of articles published in the last 5 years in two databases was performed. Of the 679 articles identified, only 27 were included and examined based on five topics, taking into account: the induction type of the breast cancer used in animal models; the characteristics of the induction model by cell transplantation; the experimental design of the ω-3 supplementation—combined or not with a treatment antitumor drug; the fatty acids (FAs) composition used; the analysis of the studies’ outcomes. There are diverse and well-established animal models of breast cancer in the literature, with very relevant histological and molecular similarities depending on the specific objective of the study, such as whether the method of tumor induction was transgenic, by cell transplantation, or by oncogenic drugs. The analyses of outcomes were mainly focused on monitoring tumor growth, body/tumor weight, and molecular, genetic, or histological analyses, and few studies evaluated latency, survival, or metastases. The best results occurred when supplementation with ω-3 PUFA was associated with antitumor drugs, especially in the analysis of metastases and volume/weight of tumors or when the supplementation was started early and maintained for a long time. However, the beneficial effect of ω-3 PUFA supplementation when not associated with an antitumor agent remains unclear.
Collapse
Affiliation(s)
| | - Mariana P. Nucci
- LIM44–Hospital das Clínicas da Faculdade Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil
| | | | | | | | | | | | | | | | | | - Lionel F. Gamarra
- Hospital Israelita Albert Einstein, São Paulo 05652-000, Brazil
- Correspondence: ; Tel.: +55-11-2151-0243
| |
Collapse
|
|
6
|
Cintoni M, Grassi F, Palombaro M, Rinninella E, Pulcini G, Di Donato A, Salvatore L, Quero G, Tortora G, Alfieri S, Gasbarrini A, Mele MC. Nutritional Interventions during Chemotherapy for Pancreatic Cancer: A Systematic Review of Prospective Studies. Nutrients 2023; 15:nu15030727. [PMID: 36771433 PMCID: PMC9920549 DOI: 10.3390/nu15030727] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/19/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Pancreatic cancer incidence is growing, but the prognosis for survival is still poor. Patients with pancreatic cancer often suffer from malnutrition and sarcopenia, two clinical conditions that negatively impact oncological clinical outcomes. The aim of this systematic review was to analyze the impact of different nutritional interventions on clinical outcomes in patients with pancreatic cancer during chemotherapy. METHODS A systematic review of MedLine, EMBASE, and Web of Science was carried out in December 2022, identifying 5704 articles. Titles and abstracts of all records were screened for eligibility based on inclusion criteria, and nine articles were included. RESULTS All nine articles included were prospective studies, but a meta-analysis could not be performed due to heterogenicity in nutritional intervention. This Systematic Review shows an improvement in Quality of Life, nutritional status, body composition, oral intake, and Karnofsky Performance Status, following nutritional interventions. CONCLUSIONS This Systematic Review in pancreatic cancer patients during chemotherapies does not allow one to draw firm conclusions. However, nutritional support in pancreatic cancer patients is advisable to ameliorate oncological care. Further well-designed prospective studies are needed to identify nutritional support's real impact and to establish a reliable way to improve nutritional status of pancreatic cancer patients during chemotherapy.
Collapse
Affiliation(s)
- Marco Cintoni
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Futura Grassi
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Marta Palombaro
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
- Correspondence: ; Tel.: +39-06-3015-3410
| | - Emanuele Rinninella
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Gabriele Pulcini
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Agnese Di Donato
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Lisa Salvatore
- Comprehensive Cancer Center, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Giuseppe Quero
- Digestive Surgery Unit, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Giampaolo Tortora
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Comprehensive Cancer Center, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Digestive Surgery Unit, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Maria Cristina Mele
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| |
Collapse
|
|
7
|
Li Y, Wang J, Wang H, Zhang S, Wei Y, Liu S. The Interplay Between Inflammation and Stromal Components in Pancreatic Cancer. Front Immunol 2022; 13:850093. [PMID: 35493517 PMCID: PMC9046560 DOI: 10.3389/fimmu.2022.850093] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/24/2022] [Indexed: 01/18/2023] Open
Abstract
Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.
Collapse
Affiliation(s)
- Ying Li
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Wang
- Department of Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiyan Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shaoqiang Zhang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yingxin Wei
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
8
|
Wei L, Wu Z, Chen YQ. Multi-targeted therapy of cancer by omega-3 fatty acids-an update. Cancer Lett 2022; 526:193-204. [PMID: 34843864 DOI: 10.1016/j.canlet.2021.11.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 12/11/2022]
Abstract
Low in dietary ω3 polyunsaturated fatty acid (PUFA) consumption has been associated with increased incidence of cancers. Many basic and clinical studies have been conducted over the last several decades. We previously reviewed multi-targeted therapy of cancer by omega-3 fatty acids in 2008, and since hundreds of new clinical trials are being conducted to validate the effectiveness of ω3 PUFA in cancer therapy. Because of the availability of such large amount of clinical trial data, in this update we summarize clinical data, sort out trials that show promising results, and discuss potential mechanism(s) responsible for the clinical outcomes. It appears that ω3 PUFA mainly affects cancer-associated symptoms, namely cachexia, inflammation, neuropathy, post operative complications and quality of life. Mechanisms responsible for these effects are possible regulation of skeletal muscle protein turnover, inflammatory response and neuron cell survive by ω3 PUFA.
Collapse
Affiliation(s)
- Lengyun Wei
- Wuxi School of Medicine, Jiangnan University, Jiangsu Province, 214122, China; Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, China; School of Food Science and Technology, Jiangnan University, Jiangsu Province, 214122, China
| | - Zhipeng Wu
- Wuxi School of Medicine, Jiangnan University, Jiangsu Province, 214122, China
| | - Yong Q Chen
- Wuxi School of Medicine, Jiangnan University, Jiangsu Province, 214122, China; Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, China; School of Food Science and Technology, Jiangnan University, Jiangsu Province, 214122, China.
| |
Collapse
|
|
9
|
Zhu Y, Li P, Meng R, Li X, Qiu Y, Wang L, Zhang S, Zhang X, Lin H, Zhai H, Liu K. Lipid Profiles of the Heads of Four Shrimp Species by UPLC-Q-Exactive Orbitrap/MS and Their Cardiovascular Activities. Molecules 2022; 27:molecules27020350. [PMID: 35056663 PMCID: PMC8781101 DOI: 10.3390/molecules27020350] [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: 11/30/2021] [Revised: 01/01/2022] [Accepted: 01/03/2022] [Indexed: 02/01/2023] Open
Abstract
Lipids are key factors in nutrition, structural function, metabolic features, and other biological functions. In this study, the lipids from the heads of four species of shrimp (Fenneropenaeus chinensis (FC), Penaeus japonicus (PJ), Penaeus vannamei (PV), and Procambarus clarkia (PCC)) were compared and characterized based on UPLC-Q-Exactive Orbitrap/MS. We compared the differences in lipid composition of four kinds of shrimp head using multivariate analysis. In addition, a zebrafish model was used to evaluate pro-angiogenic, anti-inflammatory, anti-thrombotic, and cardioprotective activities of the shrimp head lipids. The lipids from the four kinds of shrimp head had different degrees of pro-angiogenic activities, and the activities of PCC and PJ shrimp lipids were more significant than those of the other two species. Four lipid groups displayed strong anti-inflammatory activities. For antithrombotic activity, only PCC (25 μg/mL) and PV (100 μg/mL) groups showed obvious activity. In terms of cardioprotective activity, the four kinds of lipid groups significantly increased the zebrafish heart rhythms. The heart distances were shortened, except for those of the FC (100 μg/mL) and PJ (25 μg/mL) groups. Our comprehensive lipidomics analysis and bioactivity study of lipids from different sources could provide a basis for the better utilization of shrimp.
Collapse
Affiliation(s)
- Yongqiang Zhu
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
- Bioengineering Technology Innovation Center of Shandong Province, Qilu University of Technology, Shandong Academy of Sciences, Heze 274000, China
| | - Peihai Li
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
| | - Ronghua Meng
- Physical and Chemical Examination Division, Zoucheng Center for Disease Control and Prevention, Zoucheng 273500, China;
| | - Xiaobin Li
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
- Bioengineering Technology Innovation Center of Shandong Province, Qilu University of Technology, Shandong Academy of Sciences, Heze 274000, China
- Correspondence: (X.L.); (K.L.)
| | - Yuezi Qiu
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
| | - Lizheng Wang
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
| | - Shanshan Zhang
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
| | - Xuanming Zhang
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
| | - Houwen Lin
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Hongbin Zhai
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China;
| | - Kechun Liu
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Key Laboratory for Biosensor of Shandong Province, Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China; (Y.Z.); (P.L.); (Y.Q.); (L.W.); (S.Z.); (X.Z.)
- Correspondence: (X.L.); (K.L.)
| |
Collapse
|
|
10
|
Suriano F, Manca C, Flamand N, Depommier C, Van Hul M, Delzenne NM, Silvestri C, Cani PD, Di Marzo V. Exploring the endocannabinoidome in genetically obese (ob/ob) and diabetic (db/db) mice: Links with inflammation and gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1867:159056. [PMID: 34606993 DOI: 10.1016/j.bbalip.2021.159056] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/20/2021] [Accepted: 09/09/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes. RESULTS The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice. CONCLUSIONS The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations.
Collapse
Affiliation(s)
- Francesco Suriano
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium
| | - Claudia Manca
- Quebec Heart and Lung Institute Research Centre, Université Laval, Quebec City, QC G1V 0A6, Canada; Centre NUTRISS, Institute of Nutrition and Functional Foods, Université Laval, Quebec City, QC G1V 0A6, Canada
| | - Nicolas Flamand
- Quebec Heart and Lung Institute Research Centre, Université Laval, Quebec City, QC G1V 0A6, Canada
| | - Clara Depommier
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium
| | - Matthias Van Hul
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium
| | - Cristoforo Silvestri
- Quebec Heart and Lung Institute Research Centre, Université Laval, Quebec City, QC G1V 0A6, Canada; Centre NUTRISS, Institute of Nutrition and Functional Foods, Université Laval, Quebec City, QC G1V 0A6, Canada
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium.
| | - Vincenzo Di Marzo
- Quebec Heart and Lung Institute Research Centre, Université Laval, Quebec City, QC G1V 0A6, Canada; Centre NUTRISS, Institute of Nutrition and Functional Foods, Université Laval, Quebec City, QC G1V 0A6, Canada; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy.
| |
Collapse
|
|
11
|
Trestini I, Cintoni M, Rinninella E, Grassi F, Paiella S, Salvia R, Bria E, Pozzo C, Alfieri S, Gasbarrini A, Tortora G, Milella M, Mele MC. Neoadjuvant treatment: A window of opportunity for nutritional prehabilitation in patients with pancreatic ductal adenocarcinoma. World J Gastrointest Surg 2021; 13:885-903. [PMID: 34621468 PMCID: PMC8462076 DOI: 10.4240/wjgs.v13.i9.885] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/28/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Patients affected by pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced disease at the time of diagnosis, limiting an upfront surgical approach. Neoadjuvant treatment (NAT) has become the standard of care to downstage non-metastatic locally advanced PDAC. However, this treatment increases the risk of a nutritional status decline, which in turn, may impact therapeutic tolerance, postoperative outcomes, or even prevent the possibility of surgery. Literature on prehabilitation programs on surgical PDAC patients show a reduction of postoperative complications, length of hospital stay, and readmission rate, while data on prehabilitation in NAT patients are scarce and randomized controlled trials are still missing. Particularly, appropriate nutritional management represents an important therapeutic strategy to promote tissue healing and to enhance patient recovery after surgical trauma. In this regard, NAT may represent a new interesting window of opportunity to implement a nutritional prehabilitation program, aiming to increase the PDAC patient's capacity to complete the planned therapy and potentially improve clinical and survival outcomes. Given these perspectives, this review attempts to provide an in-depth view of the nutritional derangements during NAT and nutritional prehabilitation program as well as their impact on PDAC patient outcomes.
Collapse
Affiliation(s)
- Ilaria Trestini
- Section of Oncology, Department of Medicine, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Marco Cintoni
- Scuola di Specializzazione in Scienza dell’Alimentazione, Università di Roma Tor Vergata, Roma 00133, Italy
| | - Emanuele Rinninella
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli IRCCS, Roma 00168, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Futura Grassi
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli IRCCS, Roma 00168, Italy
| | - Salvatore Paiella
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Emilio Bria
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Carmelo Pozzo
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- Digestive Surgery Unit and Pancreatic Surgery Gemelli Center Director, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
| | - Giampaolo Tortora
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Maria Cristina Mele
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- UOSD Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
| |
Collapse
|
|
12
|
Gu ZT, Li ZZ, Wang CF. Research advances of intracellular mechanisms underlying gemcitabine resistance in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2020; 28:1150-1161. [DOI: 10.11569/wcjd.v28.i22.1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most deadly malignant tumors that endanger human health, and pancreatic ductal adenocarcinoma (PDAC) is the most common histological type. Due to the lack of specific clinical symptoms, physical signs, and effective screening biomarkers for early stage PDAC, only 15%-20% of patients are qualified for surgical resection. Consequently, gemcitabine (GEM)-based monotherapy or combination therapy is still the most important or even the only treatment option. However, the overall response rate of PDAC to GEM is less than 20%, and GEM resistance is one of the most important factors affecting the efficacy of chemotherapy. At present, the mechanism of GEM resistance has not been clarified, which may involve congenital and acquired regulation. The heterogeneity of PDAC further increases its complexity. However, regulation of intracellular signaling pathways is the ultimate event to induce GEM resistance. This article will review the recent advances in research of GEM metabolism and regulation of signaling pathways in PDAC cells, and discuss potential GEM chemosensitization strategies, in order to improve the effective rate of chemotherapy and the outcome.
Collapse
Affiliation(s)
- Zong-Ting Gu
- Cheng-Feng Wang, State Key Lab of Molecular Oncology & Department of Pancreatic and Gastric Surgery, National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zong-Ze Li
- Cheng-Feng Wang, State Key Lab of Molecular Oncology & Department of Pancreatic and Gastric Surgery, National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | | |
Collapse
|
|
13
|
Cancer diets for cancer patients: Lessons from mouse studies and new insights from the study of fatty acid metabolism in tumors. Biochimie 2020; 178:56-68. [PMID: 32890677 DOI: 10.1016/j.biochi.2020.08.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/29/2020] [Accepted: 08/30/2020] [Indexed: 12/15/2022]
Abstract
Specific diets for cancer patients have the potential to offer an adjuvant modality to conventional anticancer therapy. If the concept of starving cancer cells from nutrients to inhibit tumor growth is quite simple, the translation into the clinics is not straightforward. Several diets have been described including the Calorie-restricted diet based on a reduction in carbohydrate intake and the Ketogenic diet wherein the low carbohydrate content is compensated by a high fat intake. As for other diets that deviate from normal composition only by one or two amino acids, these diets most often revealed a reduction in tumor growth in mice, in particular when associated with chemo- or radiotherapy. By contrast, in cancer patients, the interest of these diets is almost exclusively supported by case reports precluding any conclusions on their real capacity to influence disease outcome. In parallel, the field of tumor lipid metabolism has emerged in the last decade offering a better understanding of how fatty acids are captured, synthesized or stored as lipid droplets in cancers. Fatty acids participate to cancer cell survival in the hypoxic and acidic tumor microenvironment and also support proliferation and invasiveness. Interestingly, while such addiction for fatty acids may account for cancer progression associated with high fat diet, it could also represent an Achilles heel for tumors. In particular n-3 polyunsaturated fatty acids represent a class of lipids that can exert potent cytotoxic effects in tumors and therefore represent an attractive diet supplementation to improve cancer patient outcomes.
Collapse
|
|
14
|
Roife D, Sarcar B, Fleming JB. Stellate Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:67-84. [PMID: 32588324 DOI: 10.1007/978-3-030-44518-8_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma.
Collapse
Affiliation(s)
- David Roife
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Bhaswati Sarcar
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
| |
Collapse
|
|
15
|
Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, Zhao F, You L, Wang W, Zhao Y. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer 2020; 19:50. [PMID: 32122374 PMCID: PMC7053123 DOI: 10.1186/s12943-020-01169-7] [Citation(s) in RCA: 239] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.
Collapse
Affiliation(s)
- Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| |
Collapse
|
|
16
|
Isherwood J, Arshad A, Chung WY, Runau F, Cooke J, Pollard C, Howells L, Fishwick J, Thompson J, Metcalfe M, Steward W, Dennison A. Myeloid derived suppressor cells are reduced and T regulatory cells stabilised in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega 3. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:172. [PMID: 32309319 PMCID: PMC7154395 DOI: 10.21037/atm.2020.02.02] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background Pancreatic adenocarcinoma (PAC) is a devastating condition, with the majority of patients presenting with metastatic or locally advanced disease. In these patients their disease is classified as advanced pancreatic cancer (APC), which is incurable and associated with survivals generally of a few months. The overall survival (OS) for pancreatic cancer has not changed significantly in the past forty years with multiple trials demonstrating disappointing results. Immune modulatory cells particularly myeloid derived suppressor cells (MDSCs) and T regulatory cells (Tregs) are important mediators in PAC. Omega 3 fatty acids (ω-3FAs) have been shown to have anti-inflammatory properties and there is now evidence demonstrating the benefit of ω-3FAs in PAC. Methods This was a single-center cohort study investigating intravenous ω-3FAs and gemcitabine chemotherapy versus gemcitabine therapy only in patients with APC. Here, we investigated levels of MDSCs and Tregs and examined how these changes correlated with survival. Results Eighteen trial and nine control patients were recruited. There was a significant benefit in progression-free survival (PFS) in trial compared to control patients (P=0.0003). Median survival in trial patients was 5.65 months compared to 1.8 months in control patients. There was no significant benefit in OS in trial compared to control patients (P=0.13). Median survival in trial patients was 7 months compared to 2.9 months in control patients. MDSCs were significantly decreased in trial patients (P=0.0001) but not control patients. Conversely Tregs were significantly increased in control patients (P=0.005) but not in trial patients. Conclusions Administration of ω-3FAs with gemcitabine chemotherapy in APC results in a significant decrease of MDSCs and stability of Tregs. This may be secondary to the reduction of pro-inflammatory mediators. A phase three randomized trial is justified to further examine these effects.
Collapse
Affiliation(s)
- John Isherwood
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Ali Arshad
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Wen Yuan Chung
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Franscois Runau
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Jill Cooke
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Cristina Pollard
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Lynne Howells
- Leicester Cancer Research Centre, Leicester Royal Infirmary, Leicester, UK
| | - Jenny Fishwick
- Leicester Cancer Research Centre, Leicester Royal Infirmary, Leicester, UK
| | - John Thompson
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Matthew Metcalfe
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - William Steward
- Leicester Cancer Research Centre, Leicester Royal Infirmary, Leicester, UK
| | - Ashley Dennison
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| |
Collapse
|
|
17
|
Di Marzo V, Silvestri C. Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome. Nutrients 2019; 11:nu11081956. [PMID: 31434293 PMCID: PMC6722643 DOI: 10.3390/nu11081956] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 12/14/2022] Open
Abstract
Lifestyle is a well-known environmental factor that plays a major role in facilitating the development of metabolic syndrome or eventually exacerbating its consequences. Various lifestyle factors, especially changes in dietary habits, extreme temperatures, unusual light-dark cycles, substance abuse, and other stressful factors, are also established modifiers of the endocannabinoid system and its extended version, the endocannabinoidome. The endocannabinoidome is a complex lipid signaling system composed of a plethora (>100) of fatty acid-derived mediators and their receptors and anabolic and catabolic enzymes (>50 proteins) which are deeply involved in the control of energy metabolism and its pathological deviations. A strong link between the endocannabinoidome and another major player in metabolism and dysmetabolism, the gut microbiome, is also emerging. Here, we review several examples of how lifestyle modifications (westernized diets, lack or presence of certain nutritional factors, physical exercise, and the use of cannabis) can modulate the propensity to develop metabolic syndrome by modifying the crosstalk between the endocannabinoidome and the gut microbiome and, hence, how lifestyle interventions can provide new therapies against cardiometabolic risk by ensuring correct functioning of both these systems.
Collapse
Affiliation(s)
- Vincenzo Di Marzo
- École de nutrition, Université Laval, Québec, QC G1V 0A6, Canada
- Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC G1V 0A6, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Québec, QC G1V 0A6, Canada
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC G1V 4G5, Canada
- Department de médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy
| | - Cristoforo Silvestri
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Québec, QC G1V 0A6, Canada.
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC G1V 4G5, Canada.
- Department de médecine, Université Laval, Québec, QC G1V 0A6, Canada.
| |
Collapse
|
|
18
|
Xu F, Song Y, Guo A. Anti-Apoptotic Effects of Docosahexaenoic Acid in IL-1β-Induced Human Chondrosarcoma Cell Death through Involvement of the MAPK Signaling Pathway. Cytogenet Genome Res 2019; 158:17-24. [PMID: 31261155 DOI: 10.1159/000500290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2018] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1β stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1β promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1β, inhibits IL-1β-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.
Collapse
|
|
19
|
Vainer N, Dehlendorff C, Johansen JS. Systematic literature review of IL-6 as a biomarker or treatment target in patients with gastric, bile duct, pancreatic and colorectal cancer. Oncotarget 2018; 9:29820-29841. [PMID: 30038723 PMCID: PMC6049875 DOI: 10.18632/oncotarget.25661] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 06/04/2018] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal cancer (GI) is a major health problem. Patients with gastric, pancreatic, colorectal, bile duct and gall bladder cancer often have advanced disease at the time of diagnosis and are generally difficult to cure, resulting in a dismal prognosis for most patients. Inflammation plays an important role in the development and growth of cancer, which has led to a growing interest in the pro-inflammatory cytokine interleukin 6 (IL-6). The aim of the present review was to evaluate the clinical use of IL-6 as a biomarker or therapeutic target in patients with GI cancer. We did a systematic review of studies (1993-2018), to assess the clinical use of IL-6 as a diagnostic, prognostic or predictive tumor biomarker or as a potential therapeutic target. This review includes 48 studies and 5316 patients. Circulating IL-6 levels appear to be an independent prognostic biomarker in patients with GI cancer, with high IL-6 levels associated with short overall survival (OS). The results for colorectal cancer were too ambiguous to give conclusive results. IL-6 seemed to be a marker for some of the clinical characteristics of GI cancer, and may have a role in the diagnostic workup in general practice. No published studies have examined the use of IL-6 as a therapeutic target in pancreatic, gastric, bile duct or colorectal cancer. In conclusion, high circulating IL-6 was associated with short OS in most studies in GI cancer patients. Whether inhibition of IL-6 would decrease GI cancer symptoms and increase quality of life is unknown.
Collapse
Affiliation(s)
- Noomi Vainer
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Dehlendorff
- Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Julia S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
20
|
Valdes S, Naguib YW, Finch RA, Baze WB, Jolly CA, Cui Z. Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2´, 2´- Difluorodeoxycytidine (DHA-dFdC). Pharm Res 2017; 34:1224-1232. [PMID: 28352993 PMCID: PMC5488709 DOI: 10.1007/s11095-017-2139-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 03/02/2017] [Indexed: 11/28/2022]
Abstract
PURPOSE This study was designed to test the short-term toxicity of DHA-dFdC in a mouse model and its efficacy in a mouse model of leukemia at or below its repeat-dose maximum tolerated dose (RD-MTD). METHOD A repeat-dose dose-ranging toxicity study was designed to determine the tolerability of DHA-dFdC when administered to DBA/2 mice by intravenous (i.v.) injection on a repeat-dose schedule (i.e. injections on days 0, 3, 7, 10, and 13). In order to determine the effect of a lethal dose of DHA-dFdC, mice were injected i.v. with three doses of DHA-dFdC at 100 mg/kg on days 0, 3, and 5 (i.e. a lethal-RD). The body weight of mice was recorded two or three times a week. At the end of the study, major organs (i.e. heart, liver, spleen, kidneys, lung, and pancreas) of mice that received the lethal-RD or RD-MTD were weighed, and blood samples were collected for analyses. Finally, DHA-dFdC was i.v. injected into DBA/2 mice with syngeneic L1210 mouse leukemia cells to evaluate its efficacy at or below RD-MTD. RESULTS The RD-MTD of DHA-dFdC is 50 mg/kg. At 100 mg/kg, a lethal-RD, DHA-dFdC decreases the weights of mouse spleen and liver and significantly affected certain blood parameters (i.e. white blood cells, lymphocytes, eosinophils, and neutrophil segmented). At or below its RD-MTD, DHA-dFdC significantly prolonged the survival of L1210 leukemia-bearing mice. CONCLUSION DHA-dFdC has dose-dependent toxicity, affecting mainly spleen at a lethal-RD. At or below its RD-MTD, DHA-dFdC is effective against leukemia in a mouse model.
Collapse
Affiliation(s)
- Solange Valdes
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA
| | - Youssef W Naguib
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA
| | - Rick A Finch
- Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas M.D. Anderson Cancer Center, Bastrop, Texas, 78602, USA
| | - Wallace B Baze
- Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas M.D. Anderson Cancer Center, Bastrop, Texas, 78602, USA
| | - Christopher A Jolly
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, Texas, 78712, USA
| | - Zhengrong Cui
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
| |
Collapse
|
|
21
|
Park M, Kim H. Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review. J Cancer Prev 2017; 22:1-5. [PMID: 28382280 PMCID: PMC5380183 DOI: 10.15430/jcp.2017.22.1.1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor of the digestive system and radical resection, which is available to very few patients, might be the only possibility for cure. Since therapeutic choices are limited at the advanced stage, prevention is more important for reducing incidence in high-risk individuals with family history of pancreatic cancer. Epidemiological studies have shown that a high consumption of fish oil or ω3-polyunsaturated fatty acids reduces the risk of pancreatic cancers. Dietary fish oil supplementation has shown to suppress pancreatic cancer development in animal models. Previous experimental studies revealed that several hallmarks of cancer involved in the pathogenesis of pancreatic cancer, such as the resistance to apoptosis, hyper-proliferation with abnormal Wnt/β-catenin signaling, expression of pro-angiogenic growth factors, and invasion. Docosahexaenoic acid (DHA) is a ω3-polyunsaturated fatty acid and rich in cold oceanic fish oil. DHA shows anti-cancer activity by inducing oxidative stress and apoptosis, inhibiting Wnt/β-catenin signaling, and decreasing extracellular matrix degradation and expression of pro-angiogenic factors in pancreatic cancer cells. This review will summarize anti-cancer mechanism of DHA in pancreatic carcinogenesis based on the recent studies.
Collapse
Affiliation(s)
- Mirae Park
- Brian Korea 21 PLUS Project, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hyeyoung Kim
- Brian Korea 21 PLUS Project, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
| |
Collapse
|
|
22
|
Pop VV, Seicean A, Lupan I, Samasca G, Burz CC. IL-6 roles - Molecular pathway and clinical implication in pancreatic cancer - A systemic review. Immunol Lett 2017; 181:45-50. [PMID: 27876525 DOI: 10.1016/j.imlet.2016.11.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 10/28/2016] [Accepted: 11/18/2016] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer has attracted a great deal of attention owing to the poor outcome, increasing prevalence in the last years and delay diagnosis. Known as a complex disease, it involves genetic mutations, changes in tumour microenvironment and inflammatory component dominated by interleukin-6 and its activated pathways, like Janus Kinase-Signal Transducer and Activator of Translation3, Mitogen Activated Protein Kinase and Androgen receptor. The pro-inflammatory cytokine, plays a central role in oncogenesis, cancer progression, invasiveness, microenvironment changes, treatment resistance, prognosis and associated co morbidities like cachexia and depression. Fulfilling these roles IL-6 requires special attention to understand its complexity in PC development.
Collapse
Affiliation(s)
- Vlad-Vasile Pop
- Iuliu Hatieganu University of Medicine and Pharmacy, Dept. Of Immunology and Allergology, Cluj-Napoca, Romania
| | - Andrada Seicean
- Iuliu Hatieganu University of Medicine and Pharmacy, Dept. Of Internal Medicine, Gastroenterology, Cluj-Napoca, Romania; Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Iulia Lupan
- Babes Bolyai University, Department of Molecular Biology, Cluj-Napoca, Romania
| | - Gabriel Samasca
- Iuliu Hatieganu University of Medicine and Pharmacy, Dept. Of Immunology and Allergology, Cluj-Napoca, Romania; Emergency Hospital for Children, Cluj-Napoca, Romania.
| | - Claudia-Cristina Burz
- Iuliu Hatieganu University of Medicine and Pharmacy, Dept. Of Immunology and Allergology, Cluj-Napoca, Romania; Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| |
Collapse
|
|
23
|
Naguib YW, Lansakara-P D, Lashinger LM, Rodriguez BL, Valdes S, Niu M, Aldayel AM, Peng L, Hursting SD, Cui Z. Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity. Neoplasia 2016; 18:33-48. [PMID: 26806350 PMCID: PMC5965255 DOI: 10.1016/j.neo.2015.11.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 11/11/2015] [Accepted: 11/11/2015] [Indexed: 12/28/2022] Open
Abstract
In this study, a new compound, 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio). DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.
Collapse
Affiliation(s)
- Youssef W Naguib
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Dharmika Lansakara-P
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Laura M Lashinger
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712
| | - B Leticia Rodriguez
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Solange Valdes
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Mengmeng Niu
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Abdulaziz M Aldayel
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712
| | - Lan Peng
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Stephen D Hursting
- Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599
| | - Zhengrong Cui
- Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
| |
Collapse
|
|
24
|
Yum HW, Na HK, Surh YJ. Anti-inflammatory effects of docosahexaenoic acid: Implications for its cancer chemopreventive potential. Semin Cancer Biol 2016; 40-41:141-159. [PMID: 27546289 DOI: 10.1016/j.semcancer.2016.08.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 08/07/2016] [Accepted: 08/16/2016] [Indexed: 12/11/2022]
Abstract
The implication of inflammatory tissue damage in pathophysiology of human cancer as well as some metabolic disorders has been under intense investigation. Numerous studies have identified a series of critical signaling molecules involved in cellular responses to inflammatory stimuli. These include nuclear factor κB, peroxisome proliferator-activated receptor γ, nuclear factor erythroid 2 p45-related factor 2 and sterol regulatory element-binding protein 1. The proper regulation of these transcription factors mediating pro- and anti-inflammatory signaling hence provides an important strategy for the chemoprevention of inflammation-associated cancer. There is compelling evidence supporting that dietary supplementation with fish oil-derived ω-3 polyunsaturated fatty acids including docosahexaenoic acid (DHA) ameliorates symptomatic inflammation associated with cancer as well as other divergent human disorders. Acute or physiologic inflammation is an essential body's first line of defence to microbial infection and tissue injuries, but it must be properly completed by a process termed 'resolution'. Failure of resolution mechanisms can result in persistence of inflammation, leading to chronic inflammatory conditions and related malignancies. The phagocytic engulfment of apoptotic neutrophils and clearance of their potentially histotoxic contents by macrophages, called efferocytosis is an essential component in resolving inflammation. Of note, DHA is a precursor of endogenous proresolving lipid mediators which regulate the leukocyte trafficking and recruitment and thereby facilitate efferocytosis. Therefore, DHA and its metabolites may have a preventive potential in the management of human cancer which arises as a consequence of impaired resolution of inflammation as well as chronic inflammation.
Collapse
Affiliation(s)
- Hye-Won Yum
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Hye-Kyung Na
- Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, Seoul, 01133, South Korea.
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 110-744, South Korea.
| |
Collapse
|
|
25
|
Abstract
Over the past decades, extensive studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 FAs) against different human diseases such as cardiovascular and neurodegenerative diseases, cancer, etc. A growing body of scientific research shows the pharmacokinetic information and safety of these natural occurring substances. Moreover, during recent years, a plethora of studies has demonstrated that omega-3 FAs possess therapeutic role against certain types of cancer. It is also known that omega-3 FAs can improve efficacy and tolerability of chemotherapy. Previous reports showed that suppression of nuclear factor-κB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of antineoplastic effect of omega-3 FAs. In this review, we have collected the available clinical data on the therapeutic role of omega-3 FAs against breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, head and neck cancer, as well as cancer cachexia. We also discussed the chemistry, dietary source, and bioavailability of omega-3 FAs, and the potential molecular mechanisms of anticancer and adverse effects.
Collapse
|
|
26
|
Arshad A, Isherwood J, Mann C, Cooke J, Pollard C, Runau F, Morgan B, Steward W, Metcalfe M, Dennison A. Intravenous ω-3 Fatty Acids Plus Gemcitabine. JPEN J Parenter Enteral Nutr 2016. [PMID: 26220200 DOI: 10.1177/0148607115595221] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Marine-derived ω-3 fatty acids (ω-3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω-3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. MATERIALS AND METHODS Patients were administered gemcitabine 1000 mg/m3 weekly followed by up to 100 g (200 mg/mL) of ω-3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. RESULTS Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease-specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). CONCLUSION Intravenous ω-3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.
Collapse
Affiliation(s)
- Ali Arshad
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - John Isherwood
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Christopher Mann
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Jill Cooke
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Cristina Pollard
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Franscois Runau
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Bruno Morgan
- 2 Department of Radiology, University Hospitals of Leicester, Leicester, UK
| | - William Steward
- 3 Department of Medical Oncology, University Hospitals of Leicester, Leicester, UK
| | - Matthew Metcalfe
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| | - Ashley Dennison
- 1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK
| |
Collapse
|
|
27
|
Abstract
Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.
Collapse
|
|
28
|
Lippitz BE, Harris RA. Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis. Oncoimmunology 2016; 5:e1093722. [PMID: 27467926 PMCID: PMC4910721 DOI: 10.1080/2162402x.2015.1093722] [Citation(s) in RCA: 172] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 09/08/2015] [Indexed: 02/09/2023] Open
Abstract
OBJECTIVE In tumor patients, IL-6 appears to be one component of a consistent cancer-associated cytokine network resulting in both a systemic immune stimulation and a microenvironment of cancer-induced immune suppression that ultimately protects the cancer cells. IL-6 has been associated with prognosis in cancer patients, but so far a systemical analysis has not been carried out. METHODS The present meta-analysis studies the relation between IL-6 serum levels and the prognosis of cancer patients in the available clinical literature of 100 articles published between 1993 and 2013 comprising 11,583 patients. RESULTS The IL-6 serum level was described as significantly correlating with survival in 82/101 series comprising 85.6% of patients (9917/11,583) with 23 different cancer types. A total of 64 studies dichotomized patient cohorts according to various cut-off IL-6 serum levels: in 59/64 of these series corresponding to 94.5% of the reported patients (7694/8142) significant correlations between IL-6 serum level and survival were seen. The median survival of cancer patients had been determined above various cut-off levels of serum IL-6 in 24 dichotomized studies (26 cohorts). There was a highly significant inverse correlation between median survival of the cohorts with IL-6 serum level above cut-off (1272 patients) and their corresponding IL-6 cut-off values (Spearman R -0,48 p= < 0.001) following a linear regression when both parameters were log-transformed (p < 0.001). A significant correlation between increasing serum IL-6 and tumor stage or metastases was described in 39/44 studies and 91% of published patients (4221/4636) where clinical parameters had been specified. CONCLUSIONS Closely associated with the patient's clinical condition and independent of the cancer histology, the increased IL-6 serum level uniformly appears to correlate with survival as paraneoplastic condition in later cancer stages independent of the cancer type. Modifications of this paraneoplastic immune reaction may offer new therapeutic options in cancer.
Collapse
Affiliation(s)
- Bodo E Lippitz
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Sjukhuset, Karolinska Institutet , Stockholm, Sweden
| | - Robert A Harris
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Sjukhuset, Karolinska Institutet , Stockholm, Sweden
| |
Collapse
|
|
29
|
CAF cellular glycolysis: linking cancer cells with the microenvironment. Tumour Biol 2016; 37:8503-14. [PMID: 27075473 DOI: 10.1007/s13277-016-5049-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/01/2016] [Indexed: 02/06/2023] Open
Abstract
Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.
Collapse
|
|
30
|
Haqq J, Howells LM, Garcea G, Dennison AR. Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem™. Mol Nutr Food Res 2015; 60:1437-47. [PMID: 26603273 DOI: 10.1002/mnfr.201500755] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/03/2015] [Accepted: 11/12/2015] [Indexed: 01/05/2023]
Abstract
SCOPE Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation. METHODS AND RESULTS Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, Lipidem™, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with Lipidem™. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by Lipidem™ alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of Lipidem™ with gemcitabine in cancer cells and PSCs. CONCLUSION Lipidem™ in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination.
Collapse
Affiliation(s)
- Jonathan Haqq
- Department of Cancer Studies, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, , University of Leicester, Leicester, LE2 7LX, United Kingdom.,Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, United Kingdom
| | - Lynne M Howells
- Department of Cancer Studies, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, , University of Leicester, Leicester, LE2 7LX, United Kingdom
| | - Giuseppe Garcea
- Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, United Kingdom
| | - Ashley R Dennison
- Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, United Kingdom
| |
Collapse
|
|
31
|
Kishi T, Nakamura A, Itasaka S, Shibuya K, Matsumoto S, Kanai M, Kodama Y, Takaori K, Mizowaki T, Hiraoka M. Pretreatment C-reactive protein level predicts outcome and patterns of failure after chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology 2015; 15:694-700. [PMID: 26601881 DOI: 10.1016/j.pan.2015.09.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 09/24/2015] [Accepted: 09/28/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES In this study we evaluated the predictive value of pretreatment C-reactive protein (CRP) levels on patterns of failure and survival outcomes in patients with locally advanced pancreatic cancer (LAPC) who received chemoradiotherapy (CRT). METHODS Data from 65 patients who underwent CRT for LAPC from July 2001 to May 2013 were retrospectively collected. Factors, including age, gender, Eastern Cooperative Oncology Group performance status (PS), histological confirmation, tumor size, tumor location, biliary drainage, stage, induction chemotherapy, CRP levels, neutrophil-to-lymphocyte ratio, platelet-lymphocyte ratio, albumin and carbohydrate antigen 19-9, were evaluated with regard to overall survival (OS) and patterns of failure using a Cox proportional hazards model. RESULTS The 1-year OS and median follow-up for all of the patients were 63.9% and 15.2 months, respectively. The median survival time and 1-year OS were 18.0 months and 72.5%, respectively, in the patients with lower CRP levels (≤3.0 mg/L), whereas 11.0 months and 30.8%, respectively, in the patients with higher CRP levels (>3.0 mg/L). Thirty-seven patients had tumor recurrence after CRT. All of the patients with higher CRP levels developed distant metastases as a primary sign of treatment failure. In a multivariate analysis, higher CRP levels were significantly correlated with distant disease-free survival (p = 0.004, HR = 4.50) and OS (p = 0.004, HR = 3.001). By contrast, local progression-free survival was not significantly different between the CRP subgroups. CONCLUSION The CRP levels were a significant predictor of survival and distant disease control for the LAPC patients who received CRT.
Collapse
Affiliation(s)
- Takahiro Kishi
- Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Akira Nakamura
- Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
| | - Satoshi Itasaka
- Department of Radiation Oncology, Kurashiki Central Hospital, Kurashiki, 710-0052, Japan
| | - Keiko Shibuya
- Department of Therapeutic Radiology, Graduate School of Medicine, Yamaguchi University, Ube, 755-8505, Japan
| | - Shigemi Matsumoto
- Department of Clinical Oncology and Pharmacogenomics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Masashi Kanai
- Department of Clinical Oncology and Pharmacogenomics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Kyoichi Takaori
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Takashi Mizowaki
- Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Masahiro Hiraoka
- Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| |
Collapse
|
|
32
|
Mohammed A, Janakiram NB, Pant S, Rao CV. Molecular Targeted Intervention for Pancreatic Cancer. Cancers (Basel) 2015; 7:1499-542. [PMID: 26266422 PMCID: PMC4586783 DOI: 10.3390/cancers7030850] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies.
Collapse
Affiliation(s)
- Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Shubham Pant
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| |
Collapse
|
|
33
|
Bapiro TE, Frese KK, Courtin A, Bramhall JL, Madhu B, Cook N, Neesse A, Griffiths JR, Tuveson DA, Jodrell DI, Richards FM. Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo. Br J Cancer 2014; 111:318-25. [PMID: 24874484 PMCID: PMC4102943 DOI: 10.1038/bjc.2014.288] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/15/2014] [Accepted: 04/30/2014] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. METHODS LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. RESULTS In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. CONCLUSIONS GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.
Collapse
Affiliation(s)
- T E Bapiro
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - K K Frese
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - A Courtin
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - J L Bramhall
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - B Madhu
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - N Cook
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - A Neesse
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - J R Griffiths
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - D A Tuveson
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - D I Jodrell
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| | - F M Richards
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK
| |
Collapse
|