The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1 alpha and vascular endothelial growth factor formation

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in tumor growth by increasing resistance to apoptosis and the production of angiogenic factors such as vascular endothelial growth factor (VEGF). HIF- 1 is a heterodimer comprised of oxygen-regulated HIF-1alpha and constitutively expressed HIF-1beta subunits. The redox protein thioredoxin-1 (Trx-1), which is found at high levels in many human cancers, increases both aerobic and hypoxia-induced HIF- 1alpha protein in cells leading to increased expression of HIF- regulated genes. We have investigated whether two cancer drugs that inhibit Trx-1 signaling, PX-12 (1-methylpropyl 2- imidazolyl disulfide) and pleurotin, decrease HIF-1alpha protein levels and the expression of downstream target genes. Treatment of MCF-7 human breast cancer and HT-29 human colon carcinoma cells with PX-12 and pleurotin prevented the hypoxia (1% oxygen)-induced increase in HIF-1a protein. HIF-1-trans- activating activity, VEGF formation, and inducible nitric oxide synthase were also decreased by treatment with PX-12 and pleurotin under hypoxic conditions. PX-12 and pleurotin also decreased HIF-1alpha protein levels and HIF-1alpha transactivation in RCC4 renal cell carcinoma cells that constitutively overexpress HIF-1alpha protein because of loss of the pVHL gene, indicating that HIF-is is inhibited independently of the pVHL pathway. HIF-1a and VEGF protein levels in MCF-7 tumor xenografts in vivo were decreased by PX- 12 treatment of mice. The results suggest that inhibition of HIF-1alpha by Trx-1 inhibitors may contribute to the growth inhibitory and antitumor activity of these agents.

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