A novel isocoumarin derivative induces mitotic phase arrest and apoptosis of human multiple myeloma cells
Kawano, T.; Agata, N.; Kharbanda, S.; Avigan, D.; Kufe, D.
Cancer ChemoTherapy and Pharmacology 59(3): 329-335
2007
ISSN/ISBN: 0344-5704
PMID: 16830153
DOI: 10.1007/s00280-006-0274-x
Accession: 012834956
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. Human U266, RPMI8226 and primary MM cells were analyzed for the effects of 185322 on cell cycle distribution, tubulin polymerization and induction of apoptosis. 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. These findings identify a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of MM cells.