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Abstract

The hypoxia inducible factor-1 (HIF-1) transcription factor is an important regulator of the cellular response to hypoxia. The activity of HIF-1 is regulated by the level of the HIF-1.alpha. subunit, HIF-1.alpha., which is rapidly degraded under normoxic conditions by the ubiquitin-proteasome pathway. HIF-1.alpha. levels increase under hypoxic conditions. Many human cancers also show constitutively increased HIF-1.alpha. levels. PX-478 or S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)ami-no]phenyl propionic acid N-oxide dihydrochloride, is a novel anticancer agent, and is capably of decreasing both constitutive and hypoxia induced HIF-1.alpha. protein levels and HIF-1 transactivation in vitro and in vivo. In method embodiments, the administration of PX-478 is independent of the pathways of HIF-1.alpha. regulation involving the von Hippel-Lindau protein and p53. PX-478 causes an increase in polyubiquitinated HIF-1.alpha. levels due to inhibition of HIF-1.alpha. deubiquitination. The levels of other proteins whose proteasomal breakdown is mediated by ubiquitination are not affected by PX-478. Deubiquitination is a novel pathway for the regulation of cellular HIF-1.alpha. levels and PX-478 is a specific inhibitor of the pathway. Therapeutic compounds for regulating cellular HIF-1.alpha. levels and methods of regulating cellular HIF-1.alpha. levels are herein provided.

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