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Autophagy inhibitors increase the susceptibility of KRAS-mutant human colorectal cancer cells to a combined treatment of 2-deoxy-D-glucose and lovastatin.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2021 Nov; Vol. 42 (11), pp. 1875-1887. Date of Electronic Publication: 2021 Feb 19. - Publication Year :
- 2021
-
Abstract
- 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 G <subscript>2</subscript> /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.<br /> (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)
- Subjects :
- Animals
Antimetabolites administration & dosage
Autophagy drug effects
Cell Survival drug effects
Cell Survival physiology
Chloroquine pharmacology
Colorectal Neoplasms drug therapy
Dose-Response Relationship, Drug
Drug Therapy, Combination
Female
HCT116 Cells
HEK293 Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation drug effects
Xenograft Model Antitumor Assays methods
Autophagy physiology
Colorectal Neoplasms genetics
Deoxyglucose administration & dosage
Lovastatin administration & dosage
Mutation genetics
Proto-Oncogene Proteins p21(ras) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 42
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 33608672
- Full Text :
- https://doi.org/10.1038/s41401-021-00612-9