Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy

Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8215-20. doi: 10.1073/pnas.0708100105. Epub 2008 Mar 31.

Abstract

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2(val19). Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cyclophosphamide / therapeutic use
  • Cyclophosphamide / toxicity
  • Cytoprotection*
  • Etoposide / therapeutic use
  • Etoposide / toxicity
  • Fasting / metabolism*
  • Female
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glucose / metabolism
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / metabolism
  • Oxidative Stress
  • Rats
  • Reactive Oxygen Species / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Etoposide
  • Cyclophosphamide
  • Glucose