Metformin is a metabolic modulator and radiosensitiser in rectal cancer

Frontiers in Oncology

Oncology

Diarmuid S. O’Ríordáin¹  Adnan Hafeez¹  Robert A. Hannon¹  Paul Neary¹  Reza Kalbassi¹  Croí E. Buckley²  Niamh Lynam-Lennon²  Fiona O’Connell²  Rebecca M. O’Brien²  John V. Reynolds²  Jacintha O’Sullivan²  Timothy S. Nugent³  Noel E. Donlon⁴  Paul H. McCormick⁵  John O. Larkin⁵  Michael E. Kelly⁵  Brian J. Mehigan⁵  Cara Dunne⁵ 

[1] Department of Surgery, Beacon Hospital, Dublin, Ireland;Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland;Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland;Department of Surgery, Beacon Hospital, Dublin, Ireland;Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland;Department of Surgery, Beacon Hospital, Dublin, Ireland;Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland;Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland;Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland;

关键词: metformin;    rectal cancer;    colorectal;    radiosensitiser;    energy metabolism;    radioresistance;   

DOI  :  10.3389/fonc.2023.1216911

 received in 2023-05-04, accepted in 2023-07-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.

【 授权许可】

Unknown   
Copyright © 2023 Buckley, O’Brien, Nugent, Donlon, O’Connell, Reynolds, Hafeez, O’Ríordáin, Hannon, Neary, Kalbassi, Mehigan, McCormick, Dunne, Kelly, Larkin, O’Sullivan and Lynam-Lennon