Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, Los Angeles, California 90089-0191, USA.
Cancer Res. 2010 Feb 15;70(4):1564-72. doi: 10.1158/0008-5472.CAN-09-3228. Epub 2010 Feb 9.
Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reducing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling proteins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by expressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals.
胰岛素样生长因子-I（IGF-I）受体抑制剂因其能够增强多种恶性细胞的杀伤作用而得到广泛研究，但 IGF-I 信号是否能使宿主和癌细胞对化疗产生差异保护尚不清楚。饥饿可以保护小鼠而不是癌细胞免受高剂量化疗[差异应激抗性（DSR）]。在这里，我们提供的证据表明，IGF-I 减少介导了部分饥饿依赖性 DSR。小鼠禁食 72 小时可使循环 IGF-I 降低 70%，IGF-I 抑制剂 IGFBP-1 的水平增加 11 倍。LID 小鼠循环 IGF-I 水平降低 70%至 80%，可抵抗四种化疗药物中的三种。IGF-I 的恢复足以逆转禁食的保护作用。用阿霉素治疗的 60%荷黑色素瘤 LID 小鼠实现了长期存活，而所有对照小鼠均因转移或化疗毒性而死亡。降低 IGF-I/IGF-I 信号可保护原代神经胶质细胞，但不能保护神经胶质瘤细胞免受环磷酰胺的侵害，并可保护小鼠胚胎成纤维细胞免受阿霉素的侵害。此外，酵母中缺乏 IGF-I 信号蛋白同源物，以一种可以通过表达组成型激活形式的 Ras 逆转的方式，对化疗依赖性 DNA 损伤具有保护作用。我们的结论是，通过降低循环 IGF-I 水平和下调原癌基因信号的机制，正常细胞和小鼠可以免受化疗依赖性损伤的保护。
