Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index.
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.
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, Los Angeles, California 90089-0191, USA.
Changhan
C
Lee
Fernando M
FM
Safdie
Lizzia
L
Raffaghello
Min
M
Wei
Federica
F
Madia
Edoardo
E
Parrella
David
D
Hwang
Pinchas
P
Cohen
Giovanna
G
Bianchi
Valter D
VD
Longo
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005215:Fasting / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D013006:Growth Hormone / Q000097:blood; D006305:Health Status Indicators; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D013217:Starvation / Q000097:blood / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology; D016896:Treatment Outcome
D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I; D003520:Cyclophosphamide; D013006:Growth Hormone