Hypoxic cancer ceils are found in all solid tumors and occur in regions where tumor growth outstrips new blood vessel formation. Hypoxic cancer cells are resistant to chemotherapy and radiation and are a major reason for the failure of cancer therapy. New knowledge of the cellular biology of the cell's response to hypoxia offers exciting new ways of attacking hypoxic cancer cells and exploiting their unique biology for selective therapy. The cells response to hypoxia is mediated by the HIF-1 transcription factor, a heterodimer composed of a hypoxia inducible HIF-.1 subunit and a constitutive HIF-1. subunit. Genes induced by HIF-1 allow the cancer cell to adapt its metabolism to the hostile anaerobic environment, to become resistant to programmed cell death (apoptosis) and to metastasize to new less hypoxic environments. HIF-1 also induces the production of a family of cytokines, including vascular endothelial growth factor (VEGF), that promote the formation of new tumor capillary blood vessels from pre-existing blood vessels (angiogenesis). We present evidence that a necessary factor for the hypoxia-induced increase in HIF-1 in cancer cells is the redox protein thioredoxin-1 (Trx-1). Trx-1 expression is increased in may human primary tumors where it is associated with aggressive tumor growth and decreased patient survival. We show that increased Trx-1 leads to increased hypoxia-induced HIF-.1 levels and HIF-1 transactivating activity, to increased expression of hypoxia induced genes such as VEGF and to increased tumor angiogenesis. The hypothesis upon which our work is based is that, acting by a redox mechanism, Trx-1 is necessary for the hypoxia-induced increase in HIF-.1 and its subsequent effects on tumor growth with increased angiogenesis. We also propose that drugs that inhibit the redox control of HIF.- will deprive the cancer cell of its hypoxic advantage and offer a novel and effective way of treating cancer. We have identified pleurotin as the first of a new class of HIF-.1 inhibitory antitumor agents that acts by inhibiting thioredoxin reductase, thus, reversing the redox effects of Trx-1 on HIF-.I. The objectives of our work are to conduct mechanistic studies of the redox regulation of HIF-.1 by Trx-1 and the inhibition of HIF-.1 by pleurotin.
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