Autophagy inhibitors increase the susceptibility of KRAS-mutant human colorectal cancer cells to a combined treatment of 2-deoxy-D-glucose and lovastatin

• 作者: Xiao-ming Huang Jia-jun Huang Jing-jing Du Na Zhang Ze Long You Yang Fang-fang Zhong Bo-wen Zheng Yun-fu Shen Zhe Huang Xiang Qin Jun-he Chen Qian-yu Lin Wan-jun Lin Wen-zhe Ma
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: Chemotherapy
• 页码范围: 1875-1887
• 页数: 13页
• 语种: 英文

摘要

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth.However,monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness.Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation.In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation)on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo.A combination of lovastatin (＞3.75 μM) and 2-deoxy-D-glucose (＞1.25 mM) synergistically reduced cell viability,arrested cells in the G2/M phase,and induced apoptosis.The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate,resulting in decreased production of ATP and lower steady-state ATP levels.Energy depletion markedly activated AMPK,inhibited mTOR and RAS signaling pathways,eventually inducing autophagy,the cellular pro-survival process under metabolic stress,whereas inhibition of autophagy by chloroquine (6.25 μM) enhanced the cytotoxic effect of the combination of Iovastatin and 2-deoxy-D-glucose.These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells.Our findings suggest that concurrently targeting glycolysis,oxidative phosphorylation,and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.