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A new anti-proliferative drug induces mitotic arrest and apoptosis in human pancreatic cancer cell lines

Other Titles
 새로운 췌장암 치료제의 개발 및 작용 기전 규명 
 College of Medicine (의과대학) 
 Department of Medical Science 
Issue Date
Pancreatic cancer is one of the most lethal diseases, which has 5-year survival rate of under 8% and the incidence almost equals to the mortality. Although many efforts to develop effective anti-pancreatic cancer drugs have been made, there are still limited therapeutic options for pancreatic cancer patients. Therefore, there is a clinical need to develop effective anti-pancreatic cancer drugs. In this study, the potential therapeutic effect of #765, a novel small molecule, was investigated in human pancreatic cancer cell lines. #765 inhibited proliferation of pancreatic cancer cells with nanomolar IC50 values. #765 exhibited more potent anti-proliferative effect than gemcitabine, which is used as a first-line drug for treating pancreatic cancer. #765 also suppressed colony formation of pancreatic cancer cells. Furthermore, #765 disrupted microtubule dynamics by promoting tubulin depolymerization and further led to mitotic arrest in pancreatic cancer cells. #765 caused phosphorylation of Histone H3 (Ser10), a mitosis-specific marker, and dephosphorylation of phospho-Cdc2 (Tyr15), a key regulatory step in promoting G2/M transition. Additionally, it was shown that #765 induced apoptosis and caused cleavage of caspase-3 and poly-(ADP-ribose) polymerase (PARP) in pancreatic cancer cells. #765 induced activation of c-Jun-NH2 terminal kinase (JNK) and treatment of JNK inhibitor SP600125 significantly reversed #765-induced cleavage of PARP. These results collectively indicate that #765 induces mitotic arrest by disrupting microtubule dynamics and further leads to JNK-mediated apoptosis in human pancreatic cancer cells. Thus, the current study suggests that #765 might be a potent novel anti-pancreatic cancer drug in the future.
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