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 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine,Macao University of Science and Technology,Macao,China

出　　处：《Acta Pharmacologica Sinica》2021年第11期1875-1887,共13页中国药理学报（英文版）

基　　金：funded by the Science and Technology Development Fund,Macao SAR,China(File no.0036/2020/A1,0013/2019/A1 and 0039/2020/A).

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(>3.75μM)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(6.25μM)enhanced the cytotoxic effect of the combination of lovastatin 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.

关 键 词：human colorectal cancers LOVASTATIN 2DG glycolysis OXPHOS AUTOPHAGY CHLOROQUINE HYDROXYCHLOROQUINE 

分 类 号：R730.5[医药卫生—肿瘤]