Pancreatic cancer, the fourth leading cause of
cancer death in the United States, has a negative prognosis because
metastasis occurs before symptoms manifest.
Leiodermatolide, a
polyketide macrolide with
antimitotic activity isolated from a deep water sponge 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 apoptosis by
leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells.
Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of
tubulin alone, while it enhances polymerization of
tubulin containing
microtubule associated proteins (MAPs). Observations through confocal microscopy show that
leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end
binding protein EB-1 showed that
leiodermatolide stopped the polymerization of
tubulin. These results suggest that
leiodermatolide may affect
tubulin dynamics without directly interacting with
tubulin and hint at a unique mechanism of action. In a mouse model of metastatic
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
leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.