A novel anti-microtubule agent with carbazole and benzohydrazide structures suppresses tumor cell growth in vivo

作者：Ohira Makoto; Iwasaki Yuka; Tanaka Chika; Kuroki Michitaka; Matsuo Naoki; Kitamura Tatsuhiko; Yukuhiro Masaki; Morimoto Hiroyuki; Pang Nisha; Liu Bei; Kiyono Tohru; Amemiya Masahide; Tanaka Kozo; Yoshida Kazumasa; Sugimoto Nozomi; Ohshima Takashi^*; Fujita Masatoshi

来源：Biochimica et Biophysica Acta-General Subjects, 2015, 1850(9): 1676-1684.

DOI：10.1016/j.bbagen.2015.04.013

• Anti-mitotic agents
• Anti-neoplastic agents
• Centrosome
• Microtubules
• Mitotic spindle

Background: The mitotic spindles are among the most successful targets of anti-cancer chemotherapy, and they still hold promise as targets for novel drugs. The anti-mitotic drugs in current clinical use, including taxanes, epothilones, vinca alkaloids, and halichondrins, are all microtubule-targeting agents. Although these drugs are effective for cancer chemotherapy, they have some critical problems; e.g., neurotoxicity caused by damage to neuronal microtubules, as well as innate or acquired drug resistance. To overcome these problems, a great deal of effort has been expended on development of novel anti-mitotics.
Methods: We identified novel microtubule-targeting agents with carbazole and benzohydrazide structures: N'-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007) and its related compounds. We investigated their activities against cancer cells using various methods including cell growth assay, immunofluorescence analysis, cell cycle analysis, tubulin polymerization assay, and tumor inhibition assay in nude mice.
Results: HND-007 inhibits tubulin polymerization in vitro and blocks microtubule formation and centrosome separation in cancer cells. Consequently, it suppresses the growth of various cancer cell lines, with IC50 values in the range 13-4.6 mu M. In addition, HND-007 can inhibit the growth of taxane-resistant cancer cells that overexpress P-glycoprotein. Finally, HND-007 can inhibit HeLa cell tumor growth in nude mice.
Conclusions and general significance: Taken together, these findings suggest that HND-007 is a promising lead compound for development of novel anti-mitotic, anti-microtubule chemotherapeutic agents.

• 出版日期2015-9