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Xu Y, Xue D, Kyani A, Bankhead A, Roy J, Ljungman M, Neamati N. First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer. ACS Pharmacol Transl Sci 2023; 6:1164-1181. [PMID: 37588763 PMCID: PMC10425995 DOI: 10.1021/acsptsci.3c00069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Indexed: 08/18/2023]
Abstract
Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) for the treatment of pancreatic cancer. The lead compound, DX2-201, suppresses the proliferation of a panel of cell lines, and a metabolically stable analogue, DX3-213B, shows significant efficacy in a syngeneic model of pancreatic cancer. Exome sequencing of six out of six clones resistant to DX2-201 revealed a pV91M mutation in NDUFS7, providing direct evidence of its drug-binding site. In combination studies, DX2-201 showed synergy with multiple metabolic modulators, select OXPHOS inhibitors, and PARP inhibitors. Importantly, a combination with 2-deoxyglucose overcomes drug resistance in vivo. This study demonstrates that an efficacious treatment for pancreatic cancer can be achieved through inhibition of OXPHOS and direct binding to NDUFS7, providing a novel therapeutic strategy for this hard-to-treat cancer.
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Affiliation(s)
- Yibin Xu
- Department
of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Ding Xue
- Department
of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Armita Kyani
- Department
of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Armand Bankhead
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Biostatistics and Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan 48109, United States
| | - Joyeeta Roy
- Department
of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Mats Ljungman
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Environmental Health Sciences, University
of Michigan, Ann Arbor, Michigan 48109, United States
| | - Nouri Neamati
- Department
of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel
Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
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Orchard SG, Lockery JE, Broder JC, Ernst ME, Espinoza S, Gibbs P, Wolfe R, Polekhina G, Zoungas S, Loomans-Kropp HA, Woods RL. Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes. JNCI Cancer Spectr 2023; 7:pkad017. [PMID: 36857596 PMCID: PMC10042437 DOI: 10.1093/jncics/pkad017] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/06/2023] [Accepted: 02/20/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Metformin and aspirin are commonly co-prescribed to people with diabetes. Metformin may prevent cancer, but in older people (over 70 years), aspirin has been found to increase cancer mortality. This study examined whether metformin reduces cancer mortality and incidence in older people with diabetes; it used randomization to 100 mg aspirin or placebo in the ASPirin in Reducing Events in the Elderly (ASPREE) trial to quantify aspirin's impact on metformin users. METHODS Analysis included community-dwelling ASPREE participants (aged ≥70 years, or ≥65 years for members of US minority populations) with diabetes. Diabetes was defined as a fasting blood glucose level greater than 125 mg/dL, self-report of diabetes, or antidiabetic medication use. Cox proportional hazards regression models were used to analyze the association of metformin and a metformin-aspirin interaction with cancer incidence and mortality, with adjustment for confounders. RESULTS Of 2045 participants with diabetes at enrollment, 965 were concurrently using metformin. Metformin was associated with a reduced cancer incidence risk (adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.51 to 0.90), but no conclusive benefit for cancer mortality (adjusted HR = 0.72, 95% CI = 0.43 to 1.19). Metformin users randomized to aspirin had greater risk of cancer mortality compared with placebo (HR = 2.53, 95% CI = 1.18 to 5.43), but no effect was seen for cancer incidence (HR = 1.11, 95% CI = 0.75 to 1.64). The possible effect modification of aspirin on cancer mortality, however, was not statistically significant (interaction P = .11). CONCLUSIONS In community-dwelling older adults with diabetes, metformin use was associated with reduced cancer incidence. Increased cancer mortality risk in metformin users randomized to aspirin warrants further investigation. ASPREE TRIAL REGISTRATION ClinicalTrials.gov ID NCT01038583.
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Affiliation(s)
- Suzanne G Orchard
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Jessica E Lockery
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
- Translational Immunology and Nanotechnology Research Theme, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
- Department of Internal Medicine, Division of Cancer Prevention and Control, Ohio State University, Columbus, OH, USA
| | - Jonathan C Broder
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Michael E Ernst
- Department of Pharmacy Practice and Science, College of Pharmacy and Department of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
| | - Sara Espinoza
- Division of Geriatrics, Gerontology and Palliative Medicine, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, and Geriatrics Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Peter Gibbs
- The Walter & Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Melbourne, VIC, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Rory Wolfe
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Galina Polekhina
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Sophia Zoungas
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Holli A Loomans-Kropp
- Department of Internal Medicine, Division of Cancer Prevention and Control, Ohio State University, Columbus, OH, USA
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA
| | - Robyn L Woods
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
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Yao K, Zheng H, Li T. Association Between Metformin Use and the Risk, Prognosis of Gynecologic Cancer. Front Oncol 2022; 12:942380. [PMID: 35898873 PMCID: PMC9309370 DOI: 10.3389/fonc.2022.942380] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/13/2022] [Indexed: 12/03/2022] Open
Abstract
Background For gynecological cancer patients, the beneficial effect of metformin use remains controversial due to inconsistent results of published articles. By conducting a meta-analysis, we aimed to evaluate the effect of metformin in reducing the risk and improving the survival of gynecological cancer among women with diabetes mellitus (DM). Methods Articles exploring association between metformin use and the risk, as well as prognosis of gynecologic cancer in DM, were searched in the databases: PubMed, Web of Science, SCOPUS, EMBASE, EBSCO, and PROQUEST. Articles were published before May 2022. All the studies were conducted using STATA 12.0 software. Results The meta-analysis showed no significant association between metformin use and risk of gynecologic cancer in DM with a random effects model [odds ratio (ORs)/relative risk (RR) = 0.91, 95% confidence intervals (CI) 0.77 to 1.08, I2 = 84.2%, p < 0.001]. Metformin use was associated with reduced overall survival (OS) and progression-free survival (PFS) of gynecologic cancer in DM with random effects models [OS: hazard ratio (HR) = 0.60, 95% CI 0.49–0.74, I2 = 55.2%, p = 0.002; PFS: HR = 0.55, 95% CI 0.33–0.91, I2 = 69.1%, p = 0.006], whereas no significant association was showed between metformin use and recurrence-free survival (RFS), as well as cancer-specific survival (CSS) of gynecologic cancer in DM with random effects models (RFS: HR = 0.60, 95% CI 0.30–1.18, I2 = 73.7%, p = 0.010; CSS: HR = 0.78, 95% CI 0.43–1.41, I2 = 72.4%, p = 0.013). Conclusions In conclusion, this meta-analysis indicated that metformin may be a useful adjuvant agent for gynecological cancer with DM, especially for patients with ovarian cancer and endometrial cancer.
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Badowska-Kozakiewicz A, Fudalej M, Kwaśniewska D, Durlik M, Nasierowska-Guttmejer A, Mormul A, Włoszek E, Czerw A, Banaś T, Deptała A. Diabetes Mellitus and Pancreatic Ductal Adenocarcinoma-Prevalence, Clinicopathological Variables, and Clinical Outcomes. Cancers (Basel) 2022; 14:cancers14122840. [PMID: 35740504 PMCID: PMC9221523 DOI: 10.3390/cancers14122840] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 06/05/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The aim of this study is to describe the prevalence of diabetes mellitus (DM) among patients with the diagnosis of pancreatic ductal adenocarcinoma (PDAC), analyse the association between the occurrence of DM and clinicopathological factors, and detect variables influencing overall survival. Diabetes mellitus is prevalent among patients with pancreatic cancer. In our study, patients with diabetes mellitus receiving palliative chemotherapy had significantly higher median OS than those without. Among variables influencing survival, TNM stage, nodal involvement, tumour site, levels of CEA and CRP were confirmed. Abstract Background: pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer-related deaths with increasing incidence and link to the onset of diabetes mellitus (DM). The aim of this study is to describe the prevalence of DM among patients with the diagnosis of PDAC, analyse the association between the occurrence of DM and clinicopathological factors, and detect variables influencing overall survival. Methods: a retrospective analysis of medical records was performed. The patients were divided into non-DM (n = 101) and DM (n = 74) groups. Statistical analysis with the usage of appropriate tests was conducted. Results: Patients in the groups of DM and NODM had significantly longer median OS than the non-DM group. Nodal involvement, tumour location, level of CEA, CRP and CRP/lymphocytes ratio were significantly associated with OS among patients with any type of DM. Neutropenia was less frequently observed in the DM group. Conclusions: DM is prevalent among patients with pancreatic cancer. In our study, patients with DM receiving palliative chemotherapy had significantly higher median OS than those without DM. The increased comprehension of the mechanisms of the relationship between DM and pancreatic cancer needs further research, which might provide avenues for the development of novel preventive and therapeutic strategies.
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Affiliation(s)
- Anna Badowska-Kozakiewicz
- Department of Cancer Prevention, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.B.-K.); (M.F.)
| | - Marta Fudalej
- Department of Cancer Prevention, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.B.-K.); (M.F.)
- Department of Oncology and Haematology, Central Clinical Hospital of the Ministry of Interior and Administration, 02-507 Warsaw, Poland;
| | - Daria Kwaśniewska
- Department of Oncology and Haematology, Central Clinical Hospital of the Ministry of Interior and Administration, 02-507 Warsaw, Poland;
| | - Marek Durlik
- Department of Gastroenterological Surgery and Transplantation, Central Clinical Hospital of the Ministry of Interior and Administration, 02-507 Warsaw, Poland;
| | - Anna Nasierowska-Guttmejer
- Department of Pathology, Central Clinical Hospital of the Ministry of Interior and Administration, 02-507 Warsaw, Poland;
| | - Agata Mormul
- Students’ Scientific Organization of Cancer Cell Biology, Department of Cancer Prevention, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.M.); (E.W.)
| | - Emilia Włoszek
- Students’ Scientific Organization of Cancer Cell Biology, Department of Cancer Prevention, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.M.); (E.W.)
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Tomasz Banaś
- Department of Gynecology and Oncology, Jagiellonian University Medical College, 31-501 Cracow, Poland;
- Department of Radiotherapy, Maria Sklodowska-Curie Institute–Oncology Centre, 31-115 Cracow, Poland
| | - Andrzej Deptała
- Department of Cancer Prevention, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.B.-K.); (M.F.)
- Department of Oncology and Haematology, Central Clinical Hospital of the Ministry of Interior and Administration, 02-507 Warsaw, Poland;
- Correspondence: ; Tel.: +48-22-5720702
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Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H. The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:467. [PMID: 35454306 PMCID: PMC9032206 DOI: 10.3390/medicina58040467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022]
Abstract
Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.
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Affiliation(s)
- Aiste Gulla
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
- Center of Visceral Medicine and Translational Research, Department of Surgery, Georgetown University Hospital, 3800 Reservoir Road Northwest BLES Building 1st. Floor, Washington, DC 20007, USA
| | - Urte Andriusaityte
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Gabrielius Tomas Zdanys
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Elena Babonaite
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Kestutis Strupas
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
| | - Helena Kelly
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland;
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Xue D, Xu Y, Kyani A, Roy J, Dai L, Sun D, Neamati N. Multiparameter Optimization of Oxidative Phosphorylation Inhibitors for the Treatment of Pancreatic Cancer. J Med Chem 2022; 65:3404-3419. [PMID: 35167303 DOI: 10.1021/acs.jmedchem.1c01934] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Targeting oxidative phosphorylation (OXPHOS) complexes is an emerging strategy to disrupt the metabolism of select cancer subtypes and to overcome resistance to targeted therapies. Here, we describe our lead optimization campaign on a series of benzene-1,4-disulfonamides as novel OXPHOS complex I inhibitors. This effort led to the discovery of compound 23 (DX3-213B) as one of the most potent complex I inhibitors reported to date. DX3-213B disrupts adenosine triphosphate (ATP) generation, inhibits complex I function, and results in the growth inhibition of pancreatic cancer cells in the low nanomolar range. Importantly, the oral administration of DX3-213B resulted in significant in vivo efficacy in a pancreatic cancer syngeneic model without obvious toxicity. Our data clearly demonstrate that OXPHOS inhibition can be a safe and efficacious strategy to treat pancreatic cancer.
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Overall Survival and Prognostic Factors among Older Patients with Metastatic Pancreatic Cancer: A Retrospective Analysis Using a Hospital Database. Cancers (Basel) 2022; 14:cancers14051105. [PMID: 35267412 PMCID: PMC8909682 DOI: 10.3390/cancers14051105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The benefits of standard treatments in metastatic pancreatic cancer (mPC) in terms of overall survival (OS) remain to date unclear, especially after 70 years. Alongside geriatric and oncologic parameters, we showed that the gemcitabine + nab-paclitaxel regimen and anti-diabetic therapy were significantly associated with a better OS, while impaired functional status, the liver metastases and high neutrophil count were associated with a worse OS in older adults with mPC. We confirm the feasibility and efficacy of chemotherapy in older adults with mPC. Abstract Pre-therapeutic factors associated with overall survival (OS) among older patients ≥70 years with metastatic pancreatic cancer (mPC) are not known. This was a retrospective single-centre cohort study in Paris including 159 consecutive older patients with mPC between 2000 and 2018. Alongside geriatric parameters, specific comorbidities, cancer-related data and chemotherapy regimens were retrieved. Cox multivariate models were run to assess predictors for OS. The median age was 80 years, 52% were women, 21.5% had diabetes, and 48% had pancreatic head cancer and 72% liver metastases. 62% of the patients (n = 99) received chemotherapy, among which the gemcitabine + nab-paclitaxel (GnP) regimen was the most frequent (72%). Median OS [95%CI] was 7.40 [5.60–10.0] and 1.40 [0.90–2.20] months respectively for patients with and without chemotherapy. The GnP regimen (aHR [95%CI] = 0.47 [0.25–0.89], p = 0.02) and diabetes (aHR = 0.44 [0.24–0.77], p = 0.004) (or anti-diabetic therapy) were multivariate protective factors for death, while ECOG-PS, liver metastases, and the neutrophil cell count were multivariate risk factors for death. In the chemotherapy group, ECOG-PS, number of metastatic sites and the GnP remained significantly associated with OS. Our study confirms the feasibility and efficacy of chemotherapy and the protective effects of diabetes among older patients with mPC.
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Diabetes and pancreatic cancer: Exploring the two-way traffic. World J Gastroenterol 2021; 27:4939-4962. [PMID: 34497428 PMCID: PMC8384733 DOI: 10.3748/wjg.v27.i30.4939] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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De Lellis L, Veschi S, Tinari N, Mokini Z, Carradori S, Brocco D, Florio R, Grassadonia A, Cama A. Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates. Cancers (Basel) 2021; 13:3946. [PMID: 34439102 PMCID: PMC8394389 DOI: 10.3390/cancers13163946] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
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Affiliation(s)
- Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Zhirajr Mokini
- European Society of Anaesthesiology and Intensive Care (ESAIC) Mentorship Programme, ESAIC, 24 Rue des Comédiens, BE-1000 Brussels, Belgium;
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Davide Brocco
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Antonino Grassadonia
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
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Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: Species with versatile therapeutic applications. Eur J Med Chem 2021; 219:113378. [PMID: 33857729 DOI: 10.1016/j.ejmech.2021.113378] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
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Affiliation(s)
- Deepika Kathuria
- University Center for Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Akshay D Raul
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Pravin Wanjari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
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11
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Zhang F, Zhong W, Li H, Huang K, Yu M, Liu Y. TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer. Front Cell Dev Biol 2021; 9:665265. [PMID: 34124046 PMCID: PMC8187932 DOI: 10.3389/fcell.2021.665265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/09/2021] [Indexed: 02/05/2023] Open
Abstract
TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)-Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.
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Affiliation(s)
- Feng Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Wenhui Zhong
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Honghao Li
- The Sixth Affiliated Hospital, Sun Yat-sen University Guangdong Gastrointestinal Hospital, Guangzhou, China
| | - Kaijun Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Yu
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Min Yu,
| | - Yubin Liu
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Yubin Liu,
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12
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Shi YQ, Zhou XC, Du P, Yin MY, Xu L, Chen WJ, Xu CF. Relationships are between metformin use and survival in pancreatic cancer patients concurrent with diabetes: A systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e21687. [PMID: 32925714 PMCID: PMC7489714 DOI: 10.1097/md.0000000000021687] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/14/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Increased risk and cancer-related mortality is observed in pancreatic cancer (PC) patients with diabetes mellitus (DM). Whether using metformin as glucose-lowering therapy can result in survival benefit in this group of patients is still unclear. METHODS A meta-analysis of 21 studies that including 38,772 patients was performed to investigate the association between metformin and overall survival in patients with PC and concurrent DM. RESULTS A significant survival benefit was observed in metformin treatment group compared with non-metformin group (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.74-0.91). These associations were observed in both subgroups of Asian countries (HR = 0.69, 95% CI: 0.60-0.79) and Western countries (HR = 0.86, 95% CI: 0.76-0.95), the former was more obvious. Survival benefit was gained for patients at early stage (HR = 0.75, 95% CI: 0.64-0.85) and mixed stage (HR = 0.81, 95% CI: 0.70-0.91), but not for patients at advanced stage (HR = 0.99, 95% CI: 0.74-1.24). Similarly, survival benefit was also observed in patients receiving surgery (HR = 0.82, 95% CI: 0.69-0.94) and comprehensive treatment (HR = 0.85, 95% CI: 0.77-0.93), but not in chemotherapy group (HR = 0.99, 95% CI: 0.67-1.30). No obvious benefit was suggested when pooled by time-varying COX model (HR = 0.94, 95% CI: 0.86-1.03). CONCLUSIONS These results suggest that metformin is associated with survival benefit in patients with PC and concurrent DM. Further randomized controlled trials and prospective studies with larger sample sizes are required to confirm our findings.
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Affiliation(s)
- Yu-Qi Shi
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University
| | | | - Peng Du
- Department of Invasive Technology, The First Affiliated Hospital of Soochow University
| | | | | | | | - Chun-Fang Xu
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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13
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Broadhurst PJ, Hart AR. An observational study to justify and plan a future phase III randomized controlled trial of metformin in improving overall survival in patients with inoperable pancreatic cancer without liver metastases. J Cancer Res Clin Oncol 2020; 146:1369-1375. [PMID: 32157435 DOI: 10.1007/s00432-020-03177-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Metformin has plausible direct and indirect anti-cancer properties against pancreatic adenocarcinoma cells. However, metformin may only be efficacious in patients with inoperable pancreatic ductal adenocarcinoma (PDAC) without liver metastases. Absorption may be decreased by gastrointestinal symptoms and proton pump inhibitors (PPIs). We aimed to justify and inform a future phase III trial of metformin versus placebo on survival in inoperable PDAC by documenting prevalence of patients meeting eligibility criteria, gastrointestinal symptoms and PPI use. METHODS Patient notes with PDAC were reviewed at a large teaching hospital over 2 years. Study variables were obtained from multiple sources of information. RESULTS 141 participants were identified (51.8% female), of which 37.6% were not prescribed metformin at diagnosis and had no radiological hepatic metastases. Characteristics were similar between non-metformin and metformin users. In eligible patients, 65.2% reported nausea and vomiting and 46.2% were prescribed PPIs. CONCLUSION Approximately, a third of all patients with inoperable PDAC are eligible for a future trial of metformin, allowing an estimate of the number of hospitals required for recruitment. Nausea and vomiting are common and should be managed effectively to prevent trial dropouts. PPI use is frequent and their influence on metformin's pharmacodynamic actions needs to be clarified.
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Affiliation(s)
| | - Andrew R Hart
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
- Norfolk and Norwich University Hospital NHS Trust, Norwich, NR4 7TJ, UK
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14
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Zhao Y, Luo Q, Mo J, Li J, Ye D, Ao Z, Chen L, Liu J. Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks. J Cancer 2020; 11:3701-3712. [PMID: 32328174 PMCID: PMC7171495 DOI: 10.7150/jca.36372] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 02/06/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin (MET) is taken as a principal medication for remedying Type 2 diabetes mellitus. Its anti-tumor effect has been reported increasingly, but the precise mechanism of it remains unclear. This study aims to explore the efficacy of MET and MET combined with nitric oxide donor prodrug JS-K on the proliferation, apoptosis, and DNA damage in human renal cell carcinoma (RCC) cells, and investigate the possible molecular mechanism involved. The cell proliferation was tested through methyl-tetrazolium assay and cell apoptosis was ascertained by flow cytometry. The dihydroethidium and JC-1 fluorescent methods were used to detect Reactive oxygen species (ROS) and mitochondrial transmembrane potential (Δψm), respectively. Proteins associated with apoptosis and DNA damage were evaluated by Western blotting. Results showed that MET and JS-K could suppress cell growth, and the inhibition concentration 50 of treatment with MET combined with JS-K (MET + JS-K) showed more toxicity than individual agents on RCC cells. This augmented toxicity was associated with intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential alteration, and induced DNA breaks. The results of Western blotting showed that the expression level of pro-apoptotic proteins, such as Bax, Bak, caspase-3, and caspase-9, was up-regulated, and the anti-apoptotic protein Bcl-2 was down-regulated after treatment using MET alone and MET + JS-K, correspondingly. Moreover, MET + JS-K inhibited the expression of cellular PCNA and Rad51, and immunofluorescence analysis of γH2AX proved that MET + JS-K enhanced DNA damage. In summary, the results of this research indicated that MET and JS-K inhibited RCC cell growth by activating ROS, targeting mitochondria-dependent apoptotic pathways, and inducing DNA breaks.
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Affiliation(s)
- Yuwan Zhao
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Qiuming Luo
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Jierong Mo
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Jianwei Li
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Dongcai Ye
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Zhixian Ao
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Lixin Chen
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Jianjun Liu
- Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
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15
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Dong TS, Chang HH, Hauer M, Lagishetty V, Katzka W, Rozengurt E, Jacobs JP, Eibl G. Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity. Am J Physiol Gastrointest Liver Physiol 2019; 317:G763-G772. [PMID: 31545922 PMCID: PMC6962494 DOI: 10.1152/ajpgi.00170.2019] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 09/11/2019] [Accepted: 09/15/2019] [Indexed: 01/31/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.
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Affiliation(s)
- Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Hui-Hua Chang
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Meg Hauer
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Venu Lagishetty
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - William Katzka
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Enrique Rozengurt
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Jonathan P Jacobs
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Guido Eibl
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
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16
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Toriola AT, Luo S, Thomas TS, Drake BF, Chang SH, Sanfilippo KM, Carson KR. Metformin Use and Pancreatic Cancer Survival among Non-Hispanic White and African American U.S. Veterans with Diabetes Mellitus. Cancer Epidemiol Biomarkers Prev 2019; 29:169-175. [DOI: 10.1158/1055-9965.epi-19-0781] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/26/2019] [Accepted: 10/29/2019] [Indexed: 11/16/2022] Open
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