Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1α activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1 alpha, and the augmented HIF-1 alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1 alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin-or hypoxia-induced HIF-1 alpha expression through an increase in ubiquitination, thereby accelerating HIF-1 alpha degradation and inhibiting HIF-1 alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1 alpha activity. CA-S6K1 overexpression reversed HIF-1 alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1 alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1 alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H2O2 production, thereby preventing H2O2-enhanced HIF-1 alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1 alpha activity and HIF-1 alpha-dependent tumor growth, which may result from a decrease in HIF-1 alpha stability through S6K1 inhibition in combination with an H2O2-scavenging effect. [Mol Cancer Ther 2009;8(10):2791-802]