The hypoxic inducible stress response as a target for cancer drug discovery

Semin Oncol. 2006 Aug;33(4):486-97. doi: 10.1053/j.seminoncol.2006.04.011.


All solid tumors experience some degree of hypoxia. The response to the stress of hypoxia is mediated in large part by the hypoxia inducible factor-1 (HIF-1) transcription factor that increases the expression of a variety of genes that allow the tumor to survive and grow in the hostile hypoxic environment. Increased tumor HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis. This has lead to the current interest in HIF-1 as a cancer drug target. HIF-1 activity in tumors depends on the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions or through the activation of oncogenes and/or inactivation of tumor-suppressor genes. HIF-1alpha level and HIF-1 activity are regulated by multiple pathways involving transcription, translation, post-translational modification, and the interaction with other transcription factors. A number of agents have been reported to block HIF-1 activity, acting on all of these mechanisms. Not all of the agents have been shown to block tumor HIF-1 activity in vivo. Some have shown marked HIF-1 inhibition and anti-tumor activity. There are agents already, or soon to be, tested in the clinic as anti-tumor inhibitors of HIF-1. The challenges will be to determine whether the effects of these agents that are seen is due to HIF-1 inhibition and to identify which patients are most likely to benefit from treatment with HIF-1 inhibitors.

Publication types

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

MeSH terms

  • Antigens, Neoplasm / metabolism*
  • Drugs, Investigational / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1 / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Ribonucleoproteins, Small Nuclear / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation


  • Antigens, Neoplasm
  • Drugs, Investigational
  • Hypoxia-Inducible Factor 1
  • Nerve Tissue Proteins
  • Ribonucleoproteins, Small Nuclear
  • SART1 protein, human
  • Tumor Suppressor Protein p53