Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-0191, USA.
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.
短期饥饿（STS）可保护正常细胞，同时使恶性细胞对高剂量化疗药物敏感，这在小鼠和可能的患者中都是如此。正常细胞的饥饿依赖性保护和恶性细胞的敏化作用部分取决于胰岛素样生长因子-1（IGF-1）和葡萄糖水平的降低。评估了具有特定宏量营养素（碳水化合物、蛋白质、脂肪）比例的热量限制饮食对接受高剂量化疗的小鼠的应激敏化标志物和保护作用的影响。我们发现，短期 CR 显著降低了葡萄糖和 IGF-1 水平，但当测试特定的宏量营养素缺乏时，只有完全缺乏蛋白质才会降低 IGF-1 水平。短期 50%CR 与严重蛋白质缺乏或生酮饮食相结合，可与标准 50%CR 一样提高化疗毒性抗性，但不会导致 STS 引起的高保护作用。值得注意的是，高蛋白饮食逆转了短期 CR 的有益效果。在胶质母细胞瘤的皮下小鼠模型中，在肿瘤可触及后，喂食低蛋白（4%热量来自蛋白质）饮食超过 20 天并不会延迟肿瘤进展。此外，在乳腺癌小鼠模型中，短期（3 天）50%CR 的周期不会增强顺铂的化疗疗效。这些结果表明，通过禁食获得的对化疗毒性的保护作用和对某些肿瘤进展的延缓作用，不能通过短期的热量和/或宏量营养素限制来实现。
