Raffaghello L, Lee C, Safdie FM, et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008 Mar 31 [Epub ahead of print] Published online on March 31, 2008
doi:10.1073/pnas.0708100105
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Proc Natl Acad Sci U S A. 2008 Mar 31 [Epub ahead of print]Related Articles, Links
Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy.
Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD.
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191.
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.
PMID: 18378900
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Starvation enhances chemotherapy
One popular approach to chemotherapy involves targeting the unique characteristics of cancer cells. Researchers have turned this idea upside down and used their knowledge of antiaging and stress-resistance systems to develop a differential stress resistance method to make the organism, but not the cancer cells, resistant to chemotherapy. Lizzia Raffaghello et al. examined the response of normal and cancer cells to chemotherapy after the cells were starved of blood or glucose. The authors found that yeast cells with antiaging genetic alterations, but without the Ras2val19 cancer gene ortholog, were 1,000 times better protected than those with the gene. They also found that normal glial cells were protected by starvation, whereas six cancerous brain cell lines remained susceptible to hydrogen peroxide or cyclophosphamide. Starvation did not block the toxicity of the drug etoposide to cancer cells that were injected into mice, but it provided remarkable protection to the mice. The mice, which had been starved for 2 days, showed no signs of toxicity to high doses of the chemotherapy drug and gained back the weight they had lost. The authors say they are making progress on methods and drugs to obtain the same anticancer effect with normal feeding.  P.D.