title: MPT0B002, a novel microtubule inhibitor, downregulates T315I mutant Bcr-Abl and induces apoptosis of imatinib-resistant chronic myeloid leukemia cells.
abstract: Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation-mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor. In this study, we evaluated its effects on the proliferation, cell cycle, and apoptosis of K562 CML cells and BaF3 cells expressing either wild-type Bcr-Abl (BaF3/p210) or T315I-mutated Bcr-Abl (BaF3/T315I). MPT0B002 inhibited cell viability in a dose-dependent manner in these cells but did not affect the proliferation of human umbilical vein endothelial cells. It disrupted tubulin polymerization and arrested cell cycle at the G2/M phase. Treatment with MPT0B002 induced apoptosis, and this induction was associated with increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, MPT0B002 can downregulate both Bcr-Abl and Bcr-Abl-T315I mRNA expressions and protein levels and the downstream signaling pathways. Taken together, our findings suggest that MPT0B002 may be considered a promising compound to downregulate not only wild type Bcr-Abl but also the T315I mutant to overcome Bcr-Abl-T315I mutation-mediated resistance in CML cells.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Yi-Yen
authors.initials: YY
authors.lastname: Yeh
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Yueh-Lun
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: John Yi-Chung
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan. cmbhhm@tmu.edu.tw.
authors.forename: Huei-Mei
authors.initials: HM
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C000626956:(1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone; D007211:Indoles; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Bcr-Abl; Chronic myeloid leukemia; MPT0B002; Microtubule inhibitor; Resistance; T315I