ELEUTHEROBIN, A NOVEL CYTOTOXIC AGENT THAT INDUCES TUBULIN POLYMERIZATION, IS SIMILAR TO PACLITAXEL (TAXOL(R))

Eleutherobin is a novel natural product isolated from a marine soft co ral that is extremely potent for inducing tubulin polymerization in vi tro and is cytotoxic for cancer cells with an IC50 similar to that of paclitaxel. This compound is cross-resistant along with other multidru g-resistant agents against P-glycoprotein-expressing cells and is cros s-resistant with paclitaxel against a cell line that has altered tubul in. In mechanistic studies, eleutherobin shares with paclitaxel the ab ility to induce tubulin polymerization in vitro and is most likely cyt otoxic by virtue of this mechanism, Human colon carcinoma cells expose d to eleutherobin contain multiple micronuclei and microtubule bundles , and they arrest in mitosis, depending on concentration, cell line, a nd length of exposure. These morphological abnormalities appearing in cultured cells are indistinguishable from those induced by paclitaxel. Electron microscopy reveals that eleutherobin induces homogeneous pop ulations of long, rigid microtubules similar to those formed by paclit axel. Thus, eleutherobin is a new chemotype with a mechanism of action similar to that of paclitaxel and, as such, has promising potential a s a new anticancer agent.