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Targeting hypoxia and angiogenesis through HIF-1alpha inhibition
(Landes Bioscience, 2005) Gil-Bazo, I. (Ignacio); Russell, J. (James); Rouzaut, A. (Ana); Montuenga-Badia, L.M. (Luis M.); Diaz-Gonzalez, J.A. (Juan Antonio)
Hypoxia is an important phenomenon in the tumor microenvironment. Hypoxic tumors are more aggressive and resistant to anti-neoplastic treatments. HIF-1alpha plays a major role in the response of tumors to hypoxia, and it is mainly responsible for the "angiogenic switch". HIF-1alpha contributes to tumor aggressiveness, invasiveness, and resistance to radiotherapy and chemotherapy. Targeting HIF-1alpha 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-1alpha. These promising drugs inhibit HIF-1alpha synthesis or transcriptional activity by blocking a variety of steps in several different signaling pathways. Blocking HIF-1alpha 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.