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Abstract
Abbreviations CDK2 Cyclin-dependent kinase 2 DNA Deoxyribonucleic acid KD Knockdown KO Knock-out MAPK Mitogen-activated protein kinase PCNA Proliferating cell nuclear antigen PPARa Peroxisome proliferator-activated receptor alpha SREBF Sterol regulatory element-binding protein gene STS Short-term starvation WT Wild type Dear Editor, Short-term fasting (up to 48 hours) activates strong physiological and molecular responses [ 1]. MC38 murine colon cancer cells were sensitized to 100 μmol/L oxaliplatin toxicity by STS (Supplementary Figure S3A), and p21 knockdown prevented this enhancing effect (Supplementary Figure S3B-F). p53 protein expression followed the same trend in MC38 cells (Supplementary Figure S3C) than in human cells, although p53 was more strongly induced with STS in MC38 cells, which might explain their enhanced sensitization to oxaliplatin treatment. When tumors reached a certain size, the mice were divided into four treatment groups: (1) saline; (2) two cycles of 7.5 mg/kg oxaliplatin; (3) two cycles of 48 hours of fasting (24 hours before and 24 hours after saline inoculation); (4) two cycles of a combination of fasting and chemotherapy. p21-WT MC38 cells responded equally to oxaliplatin treatment than to 48 hours of fasting, as already shown for other cell types [ 7], and a combination of oxaliplatin and fasting induced the strongest effect (Figure 1C and Supplementary Figure S3G). To test if the critical role of p21 could be applied to chemotherapies different from oxaliplatin, we measured cell viability of colon cancer cell lines cultured in control or STS medium and treated with increasing concentrations of 5-fluorouracil (Supplementary Figure S4A), doxorubicin (Supplementary Figure S4B) or etoposide (Supplementary Figure S4C).
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