Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers

Nat Commun. 2020 May 11;11(1):2332. doi: 10.1038/s41467-020-16243-3.

Abstract

Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Ascorbic Acid / pharmacology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Diet*
  • Disease Progression
  • Fasting / physiology*
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Iron / metabolism
  • Mice, Inbred BALB C
  • Mutation / genetics*
  • Oxaliplatin / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Reactive Oxygen Species / metabolism
  • Survival Analysis
  • Transferrin / metabolism

Substances

  • KRAS protein, human
  • Reactive Oxygen Species
  • Transferrin
  • Oxaliplatin
  • Iron
  • Heme Oxygenase-1
  • Proto-Oncogene Proteins p21(ras)
  • Ascorbic Acid