Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index.
Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index.
复制标题
DOI：
10.1158/0008-5472.can-09-3228
复制
发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Longo VD
中科院分区：
文献类型：
--
作者：
Lee C;Safdie FM;Raffaghello L;Wei M;Madia F;Parrella E;Hwang D;Cohen P;Bianchi G;Longo VD
胰岛素样生长因子-1受体（IGF-IR）抑制剂因其增强多种恶性细胞杀伤的能力而被广泛研究，但IGF-I及其受体在宿主和癌细胞对化疗的差异保护中的作用尚不清楚。我们以前表明，饥饿可以保护小鼠，但不能保护癌细胞免受高剂量化疗（差异应激抵抗，DSR）。在这里，我们提供的证据IGF-I减少介导的饥饿的影响DSR的作用。在小鼠中，72小时禁食使循环IGF-I减少70%，并使IGF-I抑制剂IGFBP-1的水平增加11倍。循环IGF-I水平降低70-80%的LID小鼠对测试的4种化疗药物中的3种具有保护作用。在禁食期间IGF-I的恢复足以逆转其保护作用。60%的荷黑色素瘤的LID小鼠用阿霉素治疗达到长期存活，而所有对照小鼠死于转移或化疗毒性。IGF-I/IGF-I信号的减少保护了原代胶质细胞，但不能保护胶质瘤细胞免受环磷酰胺的伤害，并保护小鼠胚胎成纤维细胞（MEFs）免受阿霉素诱导的DNA损伤。同样，S.缺乏IGF-I信号蛋白同源物的酿酒酵母显示出对化疗依赖性DNA损伤的保护作用，这通过癌基因同源物的表达而逆转。我们的结论是，减少循环IGF-I保护正常细胞和小鼠免受化疗依赖性DNA损伤的机制，涉及下调原癌蛋白。
Inhibitors of the insulin-like growth factor-1 receptor (IGF-IR) have been widely studied for their ability to enhance the killing of a variety of malignant cells, but the role of IGF-I and its receptor in the differential protection of host and cancer cells against chemotherapy is unknown. We previously showed that starvation protects mice but not cancer cells against high dose chemotherapy (Differential Stress Resistance, DSR). Here we provide evidence for the role of IGF-I reduction in mediating the effect of starvation in DSR. A 72-hour fast reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold in mice. LID mice, with a 70–80% reduction in circulating IGF-I levels, were protected against 3 out of 4 chemotherapy drugs tested. Restoration of IGF-I during fasting was sufficient to reverse its protective effect. 60% of melanoma-bearing LID mice treated with doxorubicin reached long-term survival whereas all control mice died of either metastases or chemo toxicity. Reduction of IGF-I/IGF-I signaling protected primary glia, but not glioma cells against cyclophosphamide and protected mouse embryonic fibroblasts (MEFs) against doxorubicin-induced DNA damage. Similarly, S. cerevisiae lacking homologues of IGF-I signaling proteins displayed protection against chemotherapy-dependent DNA damage, which was reversed by expression of an oncogene homolog. We conclude that reducing circulating IGF-I protects normal cells and mice against chemotherapy-dependent DNA damage by a mechanism that involves down-regulation of proto-oncoproteins.