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

SPECIAL FEATURE / MEDICAL SCIENCES

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

Lizzia Raffaghello*, Changhan Lee, Fernando M. Safdie, Min Wei, Federica Madia, Giovanna Bianchi*, and Valter D. Longo,
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191; and *Laboratory of Oncology, Giannina Gaslini Institute, 16147 Genova, Italy

Edited by Joan Selverstone Valentine, University of California, Los Angeles, CA, and approved February 11, 2008 (received for review August 29, 2007)

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 Ras2val19.

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.


reactive oxygen species | short-term starvation | maintenance mode



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Footnotes
Author contributions: L.R. and C.L. contributed equally to this work; L.R., C.L., F.M.S., M.W., F.M., and V.D.L. designed research; L.R., C.L., F.M.S., M.W., F.M., and G.B. performed research; L.R., C.L., F.M.S., M.W., F.M., and V.D.L. analyzed data; and L.R., C.L., and V.D.L. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

To whom correspondence should be addressed. E-mail: vlongo@usc.edu

© 2008 by The National Academy of Sciences of the USA