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Arizona Cancer Center, Tucson, Arizona 85724 [S. J. W., R. R. W., A. B., G. P.]; Natural Products Branch, National Cancer Institute, Frederick, Maryland 21702 [D. J. N.]; and ProlX Pharmaceuticals, Tucson, Arizona 85750 [D. L. K.]

² To whom requests for reprints should be addressed, at Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: (520) 626-2446; Fax: (520) 626-4848; E-mail: swelsh{at}azcc.arizona.edu

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-1 and constitutively expressed HIF-1ß 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-1 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-1 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-1 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-1 protein levels and HIF-1 trans-activation in RCC4 renal cell carcinoma cells that constitutively overexpress HIF-1 protein because of loss of the pVHL gene, indicating that HIF-1 is inhibited independently of the pVHL pathway. HIF-1 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-1 by Trx-1 inhibitors may contribute to the growth inhibitory and antitumor activity of these agents.

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