Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.
The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens.
McCarty
Mark F
MF
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, Tijuana, B.C., Mexico. mccarty@pantox.com
Barroso-Aranda
Jorge
J
Contreras
Francisco
F
D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D018943:Anthracyclines / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020156:Salicylic Acid / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D020533:Angiogenesis Inhibitors; D018943:Anthracyclines; D002301:Cardiac Glycosides; D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012838:Silymarin; D000077385:Silybin; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D004264:DNA Topoisomerases, Type I; D020156:Salicylic Acid