Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia

Abstract

Hypoxia-Inducible Factor (HIF)-1† is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia. HIF-1 is among the primary genes involved in the homeostatic process, which can increase vascularization in hypoxic areas such as localized ischemia and tumors. It is a transcription factor for dozens of target genes; HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer. With a growing understanding of the HIF-1 pathway, the inhibition and stimulation of its transcriptional activity via small molecules is now an attractive goal. Gene therapy to achieve both vessel proliferation and tumor regression has been demonstrated in animal studies but requires significant improvement and modification before becoming commercially available. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.