Abstract 3223: Severe dietary restriction enhances cancer treatment: Protecting normal cells and sensitizing malignant cells to chemotherapy by fasting

Chemotherapy is a standard treatment modality for many cancers. However, its full clinical potential is greatly limited by toxic side-effects manifested as myelosuppression, gastrointestinal damage, fatigue, and in some case even death. Therefore, strategies or interventions that can selectively protect normal cells but not cancer cells will increase the therapeutic index of chemo drugs. We have previously reported that fasting can selectively protect tumor-bearing mice but not the cancer cells from chemo toxicity by down-regulating growth factors including IGF-I and its downstream pathways involving AKT/TOR and Ras. Here, using dietary and genetic interventions in yeast, mammalian cell culture, and mice, we show evidence that fasting not only provides selective protection to normal cells but may also sensitize certain cancer cells to chemotherapy or the severe dietary restriction itself. Using mouse models of cancer, fasting for 48-hours was sufficient to drastically suppress tumor progression. In a mouse model of breast cancer, fasting alone caused more than a 50% decrease in tumor growth. Furthermore, when combined with chemotherapy, fasting sensitized cancer cells to chemo drugs and was able to further reduce tumor growth up to 90% compared to controls. In parallel, in vitro studies using these breast cancer cells revealed similar results where glucose restriction was sufficient to reduce proliferation and also sensitize the cells to 2 different types of the standard drugs for breast cancer treatment, doxorubicin and cyclophosphamide. Comparable results were obtained using mouse models of glioma, neuroblastoma and melanoma. Furthermore, in a metastatic model of melanoma, fasting/chemotherapy not only extended survival time, but also resulted in fewer organs affected by metastasis. Since chemotherapy is generally administered as a combination of drugs, we tested the effect of fasting on a cocktail of drugs in neuroblastoma-bearing mice and demonstrated significantly enhanced survival accompanied by reducing both drug toxicity and metastasis. In addition, we provide evidence that this protection is due to reduced DNA damage to normal cells. In fact, in our yeast studies, the deletion of the AKT/S6K homolog Sch9 or RAS provides enhanced protection against multiple types of chemotherapy-induced DNA mutations. Considering the global increase in elderly population and that aging is the major risk factor for cancer, differential protection of normal cells con