Daily administration of low-dose daunorubicin or doxorubicin inhibits hypoxia-inducible factor 1 and tumor vascularization

Abstract: Using a hypoxia-inducible factor 1 (HIF-1)-dependent luciferase reporter in Hep3B human hepatocellular carcinoma cells, we screened over 3,000 drugs that have been used in clinical trials and identified multiple anthracyclines as inhibitors of HIF-1 activity. Anthracyclines interfered with the ability of HIF-1 to bind to DNA. Daily injection of tumor-bearing mice with anthracyclines at low dose inhibited expression of the luciferase reporter and HIF-1 target genes that encode vascular endothelial growth factor A (VEGFA; ligand of VEGFR2), stromal-derived factor 1 (SDF-1; ligand of CXCR4), and stem cell factor (SCF; ligand of CD117) in tumor tissue. Increased numbers of circulating CXCR4+/Sca1+, VEGFR2+/CD34+, and VEGFR2+/CD117+ cells were demonstrated in immunodeficient mice bearing prostate cancer xenografts but not in tumor-bearing mice treated with anthracyclines, which also significantly inhibited angiogenesis in tumor tissue. Our findings indicate that HIF-1 inhibition underlies the anti-angiogenic effect associated with daunorubicin or doxorubicin metronomic therapy and suggest that these drugs may be particularly effective in patients with high levels of HIF-1α in their diagnostic tumor biopsy.