Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity.

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.

• Authors: Elizabeth W Newcomb
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 5 Pg. 411-9 (Jun 2004) ISSN: 0959-4973 [Print] England
• PMID: 15166614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

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

Topics

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