Therapeutic potential of natural compounds that regulate the activity of protein kinase C.

Protein kinase C (PKC) is a family of serine/threonine kinases that regulates a variety of cell functions including proliferation, gene expression, cell cycle, differentiation, cytoskeletal organization, cell migration, and apoptosis. The PKC signal transduction cascade coordinates complex physiological events including normal tissue function and repair. Disruption of the cellular environment through genetic mutation, disease, injury, or exposure to pro-oxidants, alcohol, or other insults can induce pathological PKC activation. Aberrant PKC activation can lead to diseases of cellular dysregulation such as cancer and diabetes. Can aberrant activation of PKC be reversed? Even 25 years after the identification of PKC, therapeutic regulation of PKC activity remains an emerging field. Because the function of each isoform remains to be elucidated, isoform specific control of gene expression is a current challenge. Natural compounds are important regulators of PKC activity, with both preventive and therapeutic efficacy. Antioxidants including vitamin A (retinoids), vitamin C (ascorbic acid) and vitamin E (tocopherols) show promise for reversal of PKC activation. beta-carotene and retinoids function as anticarcinogenic agents and antagonize the biological effects of pro-oxidants on PKC. Vitamin E reverses the deleterious effects of hyperglycemia and diabetes by down-regulating PKC activity. Antioxidants in red wine provide cardioprotective effects. However, alcohol consumption also induces oxidative stress and disrupts PKC and retinoid function in the fetus and the adult. This review examines modulation of PKC activity by natural compounds and pharmacologic analogues which can be used effectively to prevent or treat common diseases associated with aberrant activation of PKC.