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

Xiao-ming Huang1, Jia-jun Huang1, Jing-jing Du1, Na Zhang1, Ze Long1, You Yang1, Fang-fang Zhong1, Bo-wen Zheng1, Yun-fu Shen1, Zhe Huang1, Xiang Qin1, Jun-he Chen1, Qian-yu Lin1, Wan-jun Lin1, Wen-zhe Ma1
1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
Correspondence to: Wen-zhe Ma:,
DOI: 10.1038/s41401-021-00612-9
Received: 16 September 2020
Accepted: 9 January 2021
Advance online: 19 February 2021


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 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.
Keywords: human colorectal cancers; lovastatin; 2DG; glycolysis; OXPHOS; autophagy; chloroquine; hydroxychloroquine

Article Options

Download Citation

Cited times in Scopus