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

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

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Abstract

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 1.3-4.6 μM. 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.

Original languageEnglish
Pages (from-to)1676-1684
Number of pages9
JournalBiochimica et Biophysica Acta - General Subjects
Volume1850
Issue number9
DOIs
Publication statusPublished - May 19 2015

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All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

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