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


CONCLUSIONS
These findings identify a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of MM cells.
Kawano
Takeshi
T
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115 USA.
Agata
Naoki
N
Kharbanda
Surender
S
Avigan
David
D
Kufe
Donald
D
D050256:Antimitotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D049934:Isocoumarins / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*
D050256:Antimitotic Agents; D049934:Isocoumarins; C453300:isocoumarin NM-3