Tubulin polymerizing activity of dictyostatin-1, a polyketide of marine sponge origin

Abstract

Dictyostatin-1 had previously been isolated from a marine sponge of the genus Spongia sp. and described as a cytotoxic agent to murine and human cancer cells, but its mechanism of activity was unknown. In a routine screening assay used to detect cytotoxic compounds of marine origin, dictyostatin-1 was identified as a highly active component in an extract from a Lithistida sponge and exploration into its pharmacology was pursued. Initial studies demonstrated that dictyostatin-1 arrested cells in the G(2)/M phase of the cell cycle. Staining of these cells with antitubulin revealed cells having multiple aster formations and microtubule matrix bundling patterns similar to that seen in cells exposed to paclitaxel. Dictyostatin-1 was able to induce the polymerization of purified bovine brain tubulin in vitro and the polymerized tubulin remained stable at cold temperatures. Dictyostatin-1 also proved to be highly potent in two paclitaxel-resistant human cancer cell lines expressing active P-glycoprotein. Together, these results indicate that dictyostatin-1 is a potent inducer of tubulin polymerization and retains activity in cells expressing the P-glycoprotein efflux pump.