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

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 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 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 microM, 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.

• Authors: Toyotaka Iguchi, Tomomi Yachide-Noguchi, Yuichi Hashimoto, Sawako Nakazato, Morihiko Sagawa, Yasuo Ikeda, Masahiro Kizaki
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 21 Issue 2 Pg. 163-8 (Feb 2008) ISSN: 1107-3756 [Print] Greece
• PMID: 18204782 (Publication Type: Journal Article)

Chemical References

• 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione
• Antineoplastic Agents
• Isoindoles
• Tubulin Modulators
• Thalidomide
• Caspase 3

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Division (drug effects)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• G2 Phase (drug effects)
• Humans
• Isoindoles (chemistry, pharmacology)
• Multiple Myeloma (enzymology, pathology)
• Thalidomide (chemistry, pharmacology)
• Time Factors
• Tubulin Modulators (chemistry, pharmacology)