新辅助化学放射疗法耐药是直肠癌治疗中的一大挑战。越来越多的证据支持肿瘤对抗癌治疗存在改变能量代谢的机制，表明靶向肿瘤代谢可能具有潜在的治疗策略，以提高治疗反应。本研究探讨了二甲双胍对结直肠癌细胞的放射敏感性以及二甲双胍介导的放射增敏机制。结果表明，体外实验证明二甲双胍显著增强了放射敏感和放射耐药的结直肠癌细胞的放射敏感性。转录组和功能分析结果显示，二甲双胍在结直肠癌细胞中改变了能量代谢、线粒体功能、细胞周期分布和进程、细胞死亡和抗氧化水平。通过体外模型实验证明，二甲双胍处理显著抑制了未经治疗的直肠癌活组织的氧化磷酸化和糖酵解，而不影响非癌直肠组织的实时代谢特征。重要的是，与非癌直肠组织相比，二甲双胍处理不同程度地改变了直肠癌组织的蛋白质分泌组。这些数据共同突出了二甲双胍作为一种抗代谢放射增敏剂在直肠癌治疗中的潜在效用。

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.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.