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

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• 作者：Yukihiro Asami^a ; ^b ; ^&dagger ; ; Jae-Hyuk Jang^a ; ^&dagger ; ; Nak-Kyun Soung^a ; ^c ; Long He^a ; Dong Oh Moon^d ; Jong Won Kim^a ; Hyuncheol Oh^e ; Makoto Muroi^b ; Hiroyuki Osada^b ; Bo Yeon Kim^a ; ^c ; ^{bykim@kribb.re.kr} ; Jong Seog Ahn^a ; ^{jsahn@kribb.re.kr}
• 关键词：Protuboxepin A ; Marine fungal metabolite ; Metaphase arrest ; Chromosomal misalignment ; Tubulin
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 June, 2012
• 卷：20
• 期：12
• 页码：3799-3806
• 文件大小：2462 K

摘要

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 subG₁ population in tumor cells in a dose dependent manner. Our investigations revealed that protuboxepin A directly binds to 伪,尾-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.