Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity

Anticancer Drugs. 2004 Jun;15(5):411-9. doi: 10.1097/01.cad.0000127332.06439.47.

Abstract

Flavopiridol has potent anti-proliferative properties due to its direct action of binding to the ATP-binding pocket of cyclin-dependent kinases (cdks), and due to its indirect action reducing levels of other cyclins and cdk inhibitors, contributing to its pleiotropic effects. Flavopiridol is a potent apoptotic agent due to its ability to cause cell death in cycling as well as non-cycling tumor cells; to down-regulate important cell survival proteins, such as survivin, through inhibition of the phosphorylation of Thr34; to increase sensitivity for S phase cells to drug treatment by modulating E2F-1 transcription factor activity in tumor cells; to induce both caspase-dependent and -independent mitochondrial cell death pathways; and to inhibit the activation of p-Akt which in turn inhibits activation of NF-kappaB. Flavopiridol possesses several important anti-angiogenic activities including induction of apoptosis of endothelial cells; inhibition of the hypoxic induction of vascular endothelial growth factor and/or its production under hypoxic conditions through inhibition of HIF-1alpha transcription; and decreased secretion of matrix metalloproteinases that is linked with significant inhibition of invasive potential in Matrigel assays. Taken together, the anti-proliferative and anti-angiogenic properties of flavopiridol may contribute to its anti-tumor activities observed in several preclinical animal models of human cancers including prostate, lymphoid, head and neck, colon, and glioma. These promising preclinical observations opened the way for phase I and II clinical trials. Given the low toxicity profile of flavopiridol used as a single agent in patients, combination therapy now offers numerous opportunities in the near future to improve the efficacy of flavopiridol in the treatment of refractory cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Clinical Trials as Topic
  • Flavonoids / pharmacology*
  • Flavonoids / therapeutic use
  • Humans
  • Neoplasms / drug therapy*
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Flavonoids
  • Piperidines
  • alvocidib