Review article
Flavonoids and the inhibition of PKC and PI 3-kinase

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Abstract

Flavonoids provide a large number of interesting natural compounds that are consumed daily and exhibit more or less potent and selective effects on some signaling enzymes as well as on the growth and proliferation of certain malignant cells in vitro. Among the identified signal transducers, phosphoinositide 3-kinase (PI 3-kinase) and protein kinase C (PKC) are now considered key players in many cellular responses including cell multiplication, apoptosis, and transformation. Despite their lack of strict specificity, some flavonoids provide valuable bases for the design of analogues that could be used to specifically block particular isoforms of PI 3-kinase or PKC and their downstream-dependent cellular responses.

Section snippets

PI 3-kinases

Phosphoinositide 3-kinases are a family of enzymes that specifically catalyze the phosphorylation of inositol lipids in the D3 position of the inositol ring, generating new intracellular lipid second messengers (Fig. 2). These enzymes are activated by a large number of agonist-stimulated cell-surface receptors (Hawkins et al., 1997). It is now well established that PI 3-kinases play an essential role in cell signaling and in the regulation of a number of cellular functions, including

PI 3-kinase and flavonoids

Two PI 3-kinase inhibitors have proved valuable reagents in the discovery of several downstream effectors of these lipid kinases. The first commonly used is the fungal metabolite wortmannin, an irreversible inhibitor that seems to be quite specific at low concentrations (<20 nM). However, at higher concentrations, this compound has other targets in the cell. The second inhibitor is LY294002, a chromome synthetized using quercetin as a model (Vlahos et al., 1994). This compound competes with ATP

Pkcs

First described as a serine/threonine kinase activated by proteolysis (Takai et al., 1977), PKC was then characterized as a diacylglycerol- and phosphatidylserine-activated kinase. Its identification as the cellular receptor for tumor-promoting phorbol esters (Blumber, 1988) was at the origin of studies implicating the enzyme in growth control, differentiation, and tumorigenesis Nishizuka 1984, Nishizuka 1992. However, PKC was also described as a key regulator of various cellular responses

PKC and flavonoids

Certain flavonoids were found to inhibit various 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced cellular effects such as tumor promotion (Fujiki et al., 1986). Because PKC is considered the cellular receptor for TPA and mediates the cellular effects of this compound, the direct inhibition of purified PKC by various flavonoids was investigated Agullo et al. 1997, Ferriola et al. 1989. From these studies, flavones and flavonols appeared to be the most potent PKC (as well as PI 3-kinase)

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