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Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 3, pp 329–335 | Cite as

A novel isocoumarin derivative induces mitotic phase arrest and apoptosis of human multiple myeloma cells

  • Takeshi Kawano
  • Naoki Agata
  • Surender Kharbanda
  • David Avigan
  • Donald Kufe
Original Article

Abstract

Purpose

The isocoumarin NM-3 reverses resistance of human multiple myeloma (MM) cells to dexamethasone and is in clinical trials. In the present work, the NM-3 analog, 185322, has been studied for activity against MM cells.

Methods

Human U266, RPMI8226 and primary MM cells were analyzed for the effects of 185322 on cell cycle distribution, tubulin polymerization and induction of apoptosis.

Results

We show that, in contrast to NM-3, treatment with 185322 is associated with a marked arrest of MM cells in M phase. The results also demonstrate that treatment with 185322 is associated with a rapid decrease in tubulin assembly and an increase in Bcl-2 phosphorylation, consistent with disruption of mitosis. Our results further demonstrate that mitotic failure induced by 185322 results in activation of an apoptotic response in MM cell lines and primary MM cells. By contrast, 185322 had little if any effect on growth and survival of human carcinoma cells.

Conclusion

These findings identify a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of MM cells.

Keywords

Isocoumarins NM-3 analog Multiple myeloma Mitotic arrest Apoptosis 

Abbreviations

MM

Multiple myeloma

DEX

Dexamethasone

Notes

Acknowledgments

This work was supported by Grants CA100707 and CA42802 awarded by the National Cancer Institute. Mr. Kamal Chauhan is acknowledged for excellent technical support.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Takeshi Kawano
    • 1
  • Naoki Agata
    • 1
  • Surender Kharbanda
    • 1
  • David Avigan
    • 1
  • Donald Kufe
    • 1
  1. 1.Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA

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