title: Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.
abstract: 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.
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University Ft. Pierce, FL, 34946.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Guzmán
authors.affiliation: Eisai Research Institute of Boston Inc, Andover, MA, 01810-2441.
authors.forename: Qunli
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University Ft. Pierce, FL, 34946.
authors.forename: Tara P
authors.initials: TP
authors.lastname: Pitts
authors.affiliation: Eisai Co, Ltd, Tsukuba-Shi, Ibaraki, 300-2635, Japan.
authors.forename: Kaoru Ogawa
authors.initials: KO
authors.lastname: Mitsuhashi
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, 32827.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Baker
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University Ft. Pierce, FL, 34946.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Linley
authors.affiliation: Eisai Research Institute of Boston Inc, Andover, MA, 01810-2441.
authors.forename: Judy
authors.initials: J
authors.lastname: Oestreicher
authors.affiliation: Eisai Research Institute of Boston Inc, Andover, MA, 01810-2441.
authors.forename: Karen
authors.initials: K
authors.lastname: Tendyke
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University Ft. Pierce, FL, 34946.
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Winder
authors.affiliation: Eisai Research Institute of Boston Inc, Andover, MA, 01810-2441.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Suh
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University Ft. Pierce, FL, 34946.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Wright
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D050257:Tubulin Modulators; C559222:leiodermatolide
keywords: marine natural products; microtubule associated proteins; pancreatic cancer; tubulin dynamics