Targeting hypoxia and angiogenesis through HIF-1alpha inhibition.
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.
Diaz-Gonzalez
Juan A
JA
Molecular Pharmacology and Chemistry Program, Radiation Biophysics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, USA. diazgonj@mskcc.org
Russell
James
J
Rouzaut
Ana
A
Gil-Bazo
Ignacio
I
Montuenga
Luis
L
D015687:Cell Hypoxia / Q000502:physiology*; D018390:Gene Targeting; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control
D051793:Hypoxia-Inducible Factor 1