Targeting hypoxia and angiogenesis through HIF-1α inhibition

Abstract

Hypoxia is an important phenomenon in the tumor microenvironment. Hypoxic tumors are more aggressive and resistant to anti-neoplastic treatments. HIF-1α plays a major role in the response of tumors to hypoxia, and it is mainly responsible for the "angiogenic switch". HIF-1α contributes to tumor aggressiveness, invasiveness, and resistance to radiotherapy and chemotherapy. Targeting HIF-1α is an attractive strategy, with the potential for disrupting multiple pathways crucial for tumor growth. We review recent findings on the potential efficacy of small molecules to downregulate HIF-1α. These promising drugs inhibit HIF-1α synthesis or transcriptional activity by blocking a variety of steps in several different signaling pathways. Blocking HIF-1α activity should not only downregulate tumor angiogenesis, but also interfere with glycolytic metabolism and tumor cell growth. This strategy could also improve the efficiency of established tumor therapies. ©2005 Landes Bioscience.