Starvation and chemotherapy

ABSTRACT: Tumor chemoresistance is often associated to high aerobic glycolysis rates and reduced oxidative phosphorylation by cancer cells, a phenomenon called the “Warburg effect”. Thus, a treatment reversing the Warburg effect could decrease tumor cell survival both in the presence or absence of chemotherapy. Short-term starvation (STS) could accomplish this task since it is accompanied by a glucose and amino acid decrease and fatty acid increase, which require respiration for energy production. We tested the cytotoxicity of STS+Oxaliplatin on colon cancer cells by Trypan Blue, Carboxyfluorescein Succinimidyl ester and Annexin V staining. Reactive oxygen species production was measured by 2',7'-dichlorodihydrofluorescein diacetate staining. In vitro glucose consumption was evaluated by 18F-Fluoro-deoxyglucose uptake. Gene expression was tested by microarray analysis. Protein expression and activity were studied by western blot, proteomic analyses and spectrophotometric assays. CT26 bearing mice consumed only water for 48 hours (STS) before oxaliplatin treatment. Dynamic micro-Positron Emission Tomography and tumor growth measurements were performed. STS+Oxaliplatin cause a potent suppression of colon carcinoma growth and glucose consumption in in vitro and in vivo models. In CT26 cells, STS down-regulates aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. STS-dependent increase in O2 consumption is associated with reduced ATP synthesis and increased oxidation. In combination with chemotherapy, these effects of STS cause additive toxicity to cancer cells. Our findings indicate that during and following STS the decreased glucose levels promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE60653 | GEO | 2015/08/11

SECONDARY ACCESSION(S): PRJNA259196

REPOSITORIES: GEO