Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy.
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.
Raffaghello
Lizzia
L
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
Lee
Changhan
C
Safdie
Fernando M
FM
Wei
Min
M
Madia
Federica
F
Bianchi
Giovanna
G
Longo
Valter D
VD
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use / Q000633:toxicity; D019610:Cytoprotection; D005047:Etoposide / Q000627:therapeutic use / Q000633:toxicity; D005215:Fasting / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress; D000090063:Proto-Oncogene Mas; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species; D005047:Etoposide; D003520:Cyclophosphamide; D005947:Glucose