Targeting hypoxia and angiogenesis through HIF-1α inhibition

Hypoxia is an important phenomenon in the tumor microenvironment. Hypoxic tumors are more aggressive and resistant to anti-neoplastic treatments. HIF-1 alpha plays a major role in the response of tumors to hypoxia, and it is mainly responsible for the angiogenic switch. HIF-1 a contributes to tumor aggressiveness, invasiveness and resistance to radiotherapy and chemotherapy. Targeting HIF-1 alpha 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-1 alpha. These promising drugs inhibit HIF-1 alpha synthesis or transcriptional activity by blocking a variety of steps in several different signaling pathways. Blocking HIF-1 alpha 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.