title: An oral quinoline derivative, MPT0B392, causes leukemic cells mitotic arrest and overcomes drug resistant cancer cells.
abstract: 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.
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Min-Wu
authors.initials: MW
authors.lastname: Chao
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Han-Li
authors.initials: HL
authors.lastname: Huang
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: HuangFu
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Kai-Cheng
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Wu
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Chao-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: The Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Translational Research Center, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Mei-Jung
authors.initials: MJ
authors.lastname: Lai
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.|Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Chia-Ron
authors.initials: CR
authors.lastname: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011804:Quinolines; D050257:Tubulin Modulators; D004317:Doxorubicin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D020123:Sirolimus
keywords: MPT0B392; acute leukemia; drug resistance; mitotic arrest