HIF-1alpha and Cancer Therapy

Recent Results Cancer Res. 2010;180:15-34. doi: 10.1007/978-3-540-78281-0_3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cell Hypoxia
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Indazoles / therapeutic use
  • Mustard Compounds / therapeutic use
  • Neoplasms / drug therapy*
  • Neoplasms / etiology
  • Phenylpropionates / therapeutic use
  • Proto-Oncogene Proteins c-myc / physiology
  • Tumor Suppressor Protein p53 / physiology

Substances

  • 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
  • Histone Deacetylase Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Mustard Compounds
  • Phenylpropionates
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole