dimethylenastron and Pancreatic-Neoplasms

The mitotic kinesin Eg5 plays a critical role in bipolar spindle assembly, and its inhibitors have shown impressive anticancer activity in preclinical studies. This study was undertaken to investigate the effect of dimethylenastron, a specific inhibitor of Eg5, on the migration and invasion of pancreatic cancer cells.. Human pancreatic cancer cell lines PANC1, EPP85, BxPC3, CFPAC1, and AsPAC1 were used. Eg5 expression was examined using immunofluorescence microscopy. Cell migration and invasion were analyzed with wound healing and transwell assays. Cell proliferation was examined using sulforhodamine B and MTT assays. The binding of dimethylenastron to Eg5 was analyzed with a molecular modeling study, and the ADP release rate was examined with the MANT-ADP reagent.. Eg5 expression was 9-16-fold up-regulated in the 5 pancreatic cancer cell lines. Treatment of PANC1 pancreatic cancer cells with dimethylenastron (3 and 10 μmol/L) for 24 h suppressed the migratory ability of the cancer cells in a concentration-dependent manner. The invasion ability of the cancer cells was also reduced by the treatment. However, treatment of PANC1 cells with dimethylenastron (3 and 10 μmol/L) for 24 h had no detectable effect on their proliferation, which was inhibited when the cancer cells were treated with the drug for 72 h. Molecular modeling study showed that dimethylenastron could allosterically inhibit the motor domain ATPase of Eg5 by decreasing the rate of ADP release.. Dimethylenastron inhibits the migration and invasion of PANC1 pancreatic cancer cells, independent of suppressing the cell proliferation. The findings provide a novel insight into the mechanisms of targeting Eg5 for pancreatic cancer chemotherapy.

Topics: Allosteric Regulation; Cell Line, Tumor; Cell Movement; Humans; Kinesins; Neoplasm Invasiveness; Pancreatic Neoplasms; Quinazolines; Thiones

Pancreatic cancer is a devastating disease with a high mortality rate. Treatment of this malignancy remains a big challenge in oncology, and none of the currently available chemotherapeutic agents has a remarkable impact on improving patient survival. Consequently, it is important to explore new targets and find effective drugs for the management of this disease. Here we report that inhibition of the mitotic kinesin Eg5 by a pharmacological compound effectively prevents the proliferation of pancreatic cancer cells by halting mitotic progression, resulting in robust apoptosis. The mitotic arrest induced by this agent is attributed to its interference with spindle formation and activation of the spindle checkpoint. Impairment of the spindle checkpoint significantly compromises both mitotic arrest and apoptosis induced by the Eg5 inhibitor, suggesting the importance of the spindle checkpoint in monitoring Eg5 inhibitor sensitivity. Furthermore, treatment of nude mice bearing tumor xenografts of human pancreatic cancer results in pronounced tumor regression by triggering apoptosis. These data thus indicate Eg5 as a potential target for pancreatic cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Female; Humans; Kinesins; Mice; Mice, Nude; Pancreatic Neoplasms; Quinazolines; Thiones; Xenograft Model Antitumor Assays