Protuboxepin A, a marine fungal metabolite, inducing metaphase arrest and chromosomal misalignment in tumor cells.

Abstract

Previously we reported the identification of a new oxepin-containing diketopiperazine-type marine fungal metabolite, named protuboxepin A which showed antiproliferative activity in several cancer cell lines. In this study we elucidated the mechanism by which protuboxepin A induces cancer cell growth inhibition. Here we report that protuboxepin A induced round-up morphology, M phase arrest, and an increase in the subG(1) population in tumor cells in a dose dependent manner. Our investigations revealed that protuboxepin A directly binds to α,β-tubulin and stabilizes tubulin polymerization thus disrupting microtubule dynamics. This disruption leads to chromosome misalignment and metaphase arrest which induces apoptosis in cancer. Overall, we identified protuboxepin A as a microtubule-stabilizing agent which has a distinctly different chemical structure from previously reported microtubule inhibitors. These results indicate that protuboxepin A has a potential of being a new and effective anti-cancer drug.

• Authors: Yukihiro Asami, Jae-Hyuk Jang, Nak-Kyun Soung, Long He, Dong Oh Moon, Jong Won Kim, Hyuncheol Oh, Makoto Muroi, Hiroyuki Osada, Bo Yeon Kim, Jong Seog Ahn
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 12 Pg. 3799-806 (Jun 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22595423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Oxepins
• Tubulin
• protuboxepin A

Topics

• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Aquatic Organisms (microbiology)
• Aspergillus (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromosome Pairing (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Metaphase (drug effects)
• Microtubules (drug effects)
• Neoplasms (drug therapy, genetics, pathology)
• Oxepins (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship
• Tubulin (metabolism)