Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression

Exp Gerontol. 2013 Oct;48(10):1120-8. doi: 10.1016/j.exger.2013.02.016. Epub 2013 Feb 21.


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.

Keywords: Calorie restriction; Chemotherapy; Fasting; Insulin-like growth factor 1; Macronutrients; Protein restriction; Stress resistance; Tumor progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Blood Glucose / metabolism
  • Caloric Restriction*
  • Cisplatin / administration & dosage
  • Cisplatin / adverse effects
  • Diet, Protein-Restricted*
  • Disease Progression
  • Fasting / metabolism
  • Fasting / physiology
  • Female
  • Glioma / diet therapy*
  • Glioma / drug therapy
  • Infusions, Intravenous
  • Insulin-Like Growth Factor I / metabolism
  • Mammary Neoplasms, Experimental / diet therapy
  • Mammary Neoplasms, Experimental / drug therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Micronutrients / deficiency
  • Neoplasm Transplantation
  • Stress, Physiological / physiology
  • Treatment Outcome


  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Blood Glucose
  • Micronutrients
  • Insulin-Like Growth Factor I
  • Cisplatin