An oral quinoline derivative, MPT0B392, causes leukemic cells mitotic arrest and overcomes drug resistant cancer cells
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Min-Wu Chao1, Han-Li Huang1, Wei-Chun HuangFu1, Kai-Cheng Hsu1, Yi-Min Liu2, Yi-Wen Wu3, Chao-Feng Lin1, Yi-Lin Chen1, Mei-Jung Lai4, Hsueh-Yun Lee2, Jing-Ping Liou2, Che-Ming Teng2,5, Chia-Ron Yang3
1The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
3School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
4Translational Research Center, Taipei Medical University, Taipei 11031, Taiwan
5Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
Chia-Ron Yang, email: email@example.com
Keywords: MPT0B392, mitotic arrest, drug resistance, acute leukemia
Received: July 25, 2016 Accepted: January 23, 2017 Published: February 06, 2017
Despite great advances in the treatment of acute leukemia, a renaissance of current chemotherapy needs to be improved. The present study elucidates the underlying mechanism of a new synthetic quinoline derivative, MPT0B392 (B392) against acute leukemia and its potential anticancer effect in drug resistant cells. B392 caused mitotic arrest and ultimately led to apoptosis. It was further demonstrated to be a novel microtubule-depolymerizing agent. The effects of oral administration of B392 showed relative potent anti-leukemia activity in an in vivo xenograft model. Further investigation revealed that B392 triggered induction of the mitotic arrest, followed by mitochondrial membrane potential loss and caspases cleavage by activation of c-Jun N-terminal kinase (JNK). In addition, B392 enhanced the cytotoxicity of sirolimus in sirolimus-resistant acute leukemic cells through inhibition of Akt/mTOR pathway and Mcl-1 protein expression, and also was active in the p-glycoprotein (p-gp)-overexpressing National Cancer Institute/Adriamycin-Resistant cells with little susceptibility to p-gp. Taken together, B392 has potential as an oral mitotic drug and adjunct treatment for drug resistant cancer cells.
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