The Pharmacological Implications of Flavopiridol: An Updated Overview

Abstract

Flavopiridol is a flavone synthesized from the natural product rohitukine, which is derived from an Indian medicinal plant, namely Dysoxylum binectariferum Hiern. A deeper understanding of the biological mechanisms by which such molecules act may allow scientists to develop effective therapeutic strategies against a variety of life-threatening diseases, such as cancer, viruses, fungal infections, parasites, and neurodegenerative diseases. Mechanistic insight of flavopiridol reveals its potential for kinase inhibitory activity of CDKs (cyclin-dependent kinases) and other kinases, leading to the inhibition of various processes, including cell cycle progression, apoptosis, tumor proliferation, angiogenesis, tumor metastasis, and the inflammation process. The synthetic derivatives of flavopiridol have overcome a few demerits of its parent compound. Moreover, these derivatives have much improved CDK-inhibitory activity and therapeutic abilities for treating severe human diseases. It appears that flavopiridol has potential as a candidate for the formulation of an integrated strategy to combat and alleviate human diseases. This review article aims to unravel the potential therapeutic effectiveness of flavopiridol and its possible mechanism of action.

Keywords: anti-inflammatory; anti-metastasis; anti-viral; apoptosis; cell cycle arrest; flavones; flavopiridol.

Figure 1

The chemical structure of flavopiridol. A, B, C, and D represent the different aromatic rings present in the structure. The encircled regions mark the functional groups essential to flavopiridol’s functional activity.

Figure 2

Flavopiridol controls cell cycle progression by targeting different cyclin and CDK proteins of the G1 and G2 phases. The red arrows represent the effect of flavopiridol on the expression, and the arrow directions indicate the increase or decrease in the expression of these proteins.

Figure 3

An illustration of the apoptosis induced by flavopiridol. Flavopiridol promotes the apoptosis of tumor cells by targeting different proteins involved in the intrinsic and extrinsic apoptotic pathways. The red arrows represent the effect of flavopiridol on the expression, and the arrow directions indicate the increase or decrease in the expression of the respective proteins.

Figure 4

Schematic representation of flavopiridol targeting the regulatory molecular players of tumor metastasis. Flavopiridol mediates the inhibition of tumor metastasis by decreasing MMP proteins’ secretion via inhibition of NF-κB activity, increasing expression of E-cadherin and P-cadherin, and inhibition of wnt signaling through the inhibition of GSK3β. The red arrows represent the actions performed by flavopiridol, whereas the arrow directions indicate the increase or decrease in expression.

Figure 5

Modulation of molecular targets contributing to tumor angiogenesis by flavopiridol. Flavopiridol inhibits the formation of new blood vessels by targeting different signaling pathways, including decreasing VEGF secretion, suppressing MAPK pathways by inhibiting c-Jun and c-Fos transcription factors, and decreasing the secretion of MMP proteins. The red arrows here represent the actions performed by flavopiridol, whereas the arrow directions indicate the increase or decrease in expression.

Figure 6

Schematic representation of the anti-inflammatory activity of flavopiridol expression. Flavopiridol exerts its anti-inflammatory effects by targeting proteins of different cell signaling pathways, such as NF-κB, JAK-STAT, MAPK, PI-3K, and PKC. The red arrows here represent the actions performed by flavopiridol, whereas the arrow directions indicate the increase or decrease in expression.