Starvation-dependent differential Stress resistance

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)


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 pro- vided complete protection to mice but not to injected neuroblas- toma 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.