Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity International Journal of Cancer

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasisoccurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep watersponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1,PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apopto-sis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrestbut has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulincontaining microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, atlow concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphasecells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule net-work is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affecttubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of met-astatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls.The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leio-dermatolide an interesting compound with potential chemotherapeutic effects that may merit further research. Grant no. NA09OAR4320073