title: Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression.
abstract: Short-term starvation (STS) protects normal cells while simultaneously sensitizing malignant cells to high-dose chemotherapeutic drugs in mice and possibly patients. The fasting-dependent protection of normal cells and sensitization of malignant cells depends, in part, on reduced levels of insulin-like growth factor-1 (IGF-1) and glucose. Calorie restricted diets with defined macronutrient (carbohydrate, protein, fat) ratios were evaluated for the effects on stress sensitization markers and protection in mice treated with high-dose chemotherapy. We show that short-term CR significantly reduced both glucose and IGF-1 levels, but when specific macronutrient deficiencies were tested, only the complete lack of proteins reduced IGF-1 levels. Short-term 50% CR combined with either severe protein-deficiency or ketogenic diets improved chemotoxicity resistance similarly to the standard 50% CR, but did not result in the high protection caused by STS. Notably, a high protein diet reversed the beneficial effects of short-term CR. In a subcutaneous mouse model of glioma, feeding a low protein (4% calories from protein) diet for more than 20days did not delay tumor progression once the tumor became palpable. Also, cycles of short-term (3days) 50% CR did not augment the chemotherapy efficacy of cisplatin in a murine breast cancer model. These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction.
authors: Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-0191, USA.
authors: Sebastian
authors: S
authors: Brandhorst
authors: Min
authors: M
authors: Wei
authors: Saewon
authors: S
authors: Hwang
authors: Todd E
authors: TE
authors: Morgan
authors: Valter D
authors: VD
authors: Longo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001786:Blood Glucose / Q000378:metabolism; D031204:Caloric Restriction; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D018753:Diet, Protein-Restricted; D018450:Disease Progression; D005215:Fasting / Q000378:metabolism / Q000502:physiology; D005260:Female; D005910:Glioma / Q000178:diet therapy* / Q000188:drug therapy; D007262:Infusions, Intravenous; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000178:diet therapy / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018977:Micronutrients / Q000172:deficiency; D009368:Neoplasm Transplantation; D013312:Stress, Physiological / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001786:Blood Glucose; D018977:Micronutrients; D007334:Insulin-Like Growth Factor I; D002945:Cisplatin
keywords: Calorie restriction; Chemotherapy; Fasting; Insulin-like growth factor 1; Macronutrients; Protein restriction; Stress resistance; Tumor progression