Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide

  • Authors:
    • Toyotaka Iguchi
    • Tomomi Yachide-Noguchi
    • Yuichi Hashimoto
    • Sawako Nakazato
    • Morihiko Sagawa
    • Yasuo Ikeda
    • Masahiro Kizaki
  • View Affiliations

  • Published online on: February 1, 2008     https://doi.org/10.3892/ijmm.21.2.163
  • Pages: 163-168
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Abstract

To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 μM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 μM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 μM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.

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February 2008
Volume 21 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Iguchi T, Yachide-Noguchi T, Hashimoto Y, Nakazato S, Sagawa M, Ikeda Y and Kizaki M: Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide. Int J Mol Med 21: 163-168, 2008
APA
Iguchi, T., Yachide-Noguchi, T., Hashimoto, Y., Nakazato, S., Sagawa, M., Ikeda, Y., & Kizaki, M. (2008). Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide. International Journal of Molecular Medicine, 21, 163-168. https://doi.org/10.3892/ijmm.21.2.163
MLA
Iguchi, T., Yachide-Noguchi, T., Hashimoto, Y., Nakazato, S., Sagawa, M., Ikeda, Y., Kizaki, M."Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide". International Journal of Molecular Medicine 21.2 (2008): 163-168.
Chicago
Iguchi, T., Yachide-Noguchi, T., Hashimoto, Y., Nakazato, S., Sagawa, M., Ikeda, Y., Kizaki, M."Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide". International Journal of Molecular Medicine 21, no. 2 (2008): 163-168. https://doi.org/10.3892/ijmm.21.2.163