Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2021; 27(17): 1883-1904
Published online May 7, 2021. doi: 10.3748/wjg.v27.i17.1883
Repurposing metformin for the treatment of gastrointestinal cancer
Ademar Dantas Cunha Júnior, Arinilda Campos Bragagnoli, Felipe Osório Costa, José Barreto Campello Carvalheira
Ademar Dantas Cunha Júnior, Felipe Osório Costa, José Barreto Campello Carvalheira, Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
Arinilda Campos Bragagnoli, Division of Oncology, Hospital de Câncer de Barretos, Barretos 14784-400, São Paulo, Brazil
Author contributions: Cunha Junior AD, Bragagnoli AC, Costa FO and Carvalheira JBC developed the concept and design for this review; Cunha Junior AD, Bragagnoli AC and Costa FO collected and assembled the data; Cunha Junior AD, Bragagnoli AC, Costa FO and Carvalheira JBC led the writing and were responsible for critical revisions; all authors contributed to data analysis and interpretation, creation of figures and tables, and preparation of the report for publication and they approved the final version of the manuscript.
Conflict-of-interest statement: None of the authors have any conflict of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: José Barreto Campello Carvalheira, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Tessália Vieira Camargo, S/N, Campinas 13083-970, São Paulo, Brazil.
Received: January 22, 2021
Peer-review started: January 22, 2021
First decision: February 28, 2021
Revised: March 13, 2021
Accepted: April 7, 2021
Article in press: April 7, 2021
Published online: May 7, 2021

Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.

Keywords: Antidiabetic treatments, Gastrointestinal tumors, Therapeutic target

Core Tip: Modulation of cell function into the neoplastic and around the microenvironment tissue are possible cancer targets utilized by metformin to raise chemotherapy's anti-tumor outcomes. Herein we review the studies that have demonstrated the likelihood of metformin as chemo and radiosensitizer, in addition to its chemopreventive and direct therapeutic activity in gastrointestinal tumors.