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• W2019849143 abstract "as amifostine, glutathione, mesna, and dexrazoxane have been investigated and shown to provide drug-dependent protection to specific tissues, but the use of these compounds has not been shown to increase disease-free or overall survival. We previously showed that fasting selectively protects mice, and possibly patients, but not tumors against high-dose chemotherapy (Differential Stress Resistance, DSR). Here we show that the beneficial effect of fasting extends beyond protecting normal cells to sensitizing malignant cells to chemotherapy. Further, we show that the differential protection of normal cells and sensitization of malignant cells by fasting is mediated by reduced IGF-I levels/signaling. A 72-hour fast provided remarkable protection against doxorubicin. We observed that fasting 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 chemotoxicity. In both our fasted (72 hours) and LID mice, we observed a 40% decrease in IGFBP-3 levels. Therefore, to test if reduced IGFBP-3 levels mediated DSR, we challenge transgenic IGFBP-3 knockout mice (IGFBP3KO) with cyclophosphamide. We found no significant difference in survival between WT and IGFBP3KO mice, suggesting a larger role of IGF-I in mediating DSR independently of IGFBP-3. 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. On the contrary, in malignant cells, the addition of IGF-I during fasting was sufficient to reverse the sensitization to chemotherapy in vitro. Similarly, S. cerevisiae lacking homologues of IGF-I signaling proteins displayed protection against chemotherapydependent DNA damage, which was reversed by expression of an oncogene homolog. Our studies suggest that fasting has the potential to protect patients and sensitize cancer cells, in part, by reducing IGF-I levels/signaling, thereby increasing the therapeutic index of toxic drugs commonly used in the treatment of a wide range of malignancies." @default.
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• W2019849143 date "2010-01-01" @default.
• W2019849143 modified "2023-09-26" @default.
• W2019849143 title "OR13,77 Insulin-like growth factors (IGFs) and IGF binding proteins in PSA-detected prostate cancer: a population-based case control study" @default.
• W2019849143 doi "https://doi.org/10.1016/s1096-6374(10)70093-9" @default.
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