Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration and cancer. HIF-1, a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis and cell survival. Py-Im polyamide 1 has been shown to inhibit HIF-1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels and suppresses tumor growth. Tumors treated with 1 show no increase in HIF-1a and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF-1a positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF-1 has potent anti-tumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response.
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