title: HIF-1alpha and cancer therapy.
abstract: Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.
authors.affiliation: Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mei Yee
authors.initials: MY
authors.lastname: Koh
authors.forename: Taly R
authors.initials: TR
authors.lastname: Spivak-Kroizman
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007191:Indazoles / Q000627:therapeutic use; D009150:Mustard Compounds / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology; D010666:Phenylpropionates / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D009150:Mustard Compounds; D010666:Phenylpropionates; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole