Received for publication March 26, 2004.
Revised October 26, 2004.
Accepted for publication November 5, 2004.

Membrane Structure Modulation, PKC Activation and Anti-Cancer Activity of Minerval

Abstract

Most drugs currently used for human therapy interact with proteins, altering their activity to modulate the pathologic-cell physiology. In contrast, Minerval was designed to modify the lipid organization of the membrane. Its structure was deduced following the guidelines of the mechanism of action previously proposed by us for certain anti-tumor drugs. The anti-proliferative activity of Minerval supports the above hypothesis. This molecule augments the propensity of membrane lipids to organize into nonlamellar (hexagonal H_II) phases, promoting the subsequent recruitment of protein kinase C (PKC) to the cell membrane. The binding of the enzyme to membranes was marked and significantly elevated by Minerval in model (liposomes) and cell (A549) membranes and in heart membranes from animals treated with this drug. In addition, Minerval induced increased PKC expression (mRNA and protein levels) in A549 cells. This drug also induced PKC activation, which led to a p53-independent increase in p21^CIP expression, followed by a decrease in the cellular concentrations of cyclins A, B and D3 and cdk2. These molecular changes impaired the cell cycle progression of A549 cells. At the cellular and physiological level, administration of Minerval inhibited the growth of cancer cells and exerted anti-tumor effects in animal models of cancer without apparent histological toxicity. The present results support the potential use of Minerval and related compounds in the treatment of tumor pathologies.

Key words: Protein Kinase C, G protein regulation, Lipid rafts/microdomains, Regulation of gene expression, X-ray crystallography, Membrane targets