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Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.
- Source :
-
International journal of cancer [Int J Cancer] 2016 Nov 01; Vol. 139 (9), pp. 2116-26. Date of Electronic Publication: 2016 Jul 19. - Publication Year :
- 2016
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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.<br />Competing Interests: ◆ Conflict of Interest Disclosure: Guzmán, Pitts, Linley, Winder, Baker and Wright have no conflicts of interest to disclose. Xu, Tendyke, Oestreicher, Mitsuhashi and Suh are either current or former employees of Eisai, Inc.<br /> (© 2016 UICC.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Gene Expression Regulation, Neoplastic drug effects
HeLa Cells
Humans
Macrolides pharmacology
Mice
Microtubule-Associated Proteins metabolism
Neoplasm Metastasis
Pancreatic Neoplasms metabolism
Tubulin Modulators pharmacology
Xenograft Model Antitumor Assays
Antineoplastic Agents administration & dosage
Macrolides administration & dosage
Microtubules drug effects
Pancreatic Neoplasms drug therapy
Tubulin Modulators administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 139
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 27376928
- Full Text :
- https://doi.org/10.1002/ijc.30253