Anthracycline Chemotherapy Inhibits Hif-1transcriptional Activity And Tumor-inducedrnmobilization Of Circulating Angiogenic Cells

摘要

Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemothera-peutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4~+/sca1~+, VEGFR2~+/CD34~+, and VEGFR2~+/ CD117~+ bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively.