title: A novel tubulin polymerization inhibitor, MPT0B206, downregulates Bcr-Abl expression and induces apoptosis in imatinib-sensitive and imatinib-resistant CML cells.
abstract: Imatinib, a Bcr-Abl-specific inhibitor, is effective for treating chronic myeloid leukemia (CML), but drug resistance has emerged for this disease. In this study, we synthesized a novel tubulin polymerization inhibitor, MPT0B206 (N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-formamide), and demonstrated its apoptotic effect and mechanism in imatinib-sensitive K562 and imatinib-resistant K562R CML cells. Western blotting and immunofluorescence microscopy showed that MPT0B206 induced microtubule depolymerization in K562 and K562R cells. MPT0B206 inhibited the growth of these cells in a concentration- and time-dependent manner. It did not affect the viability of normal human umbilical vein endothelial cells. MPT0B206 induced G2/M cell cycle arrest and the appearance of the mitotic marker MPM-2 in K562 and K562R cells, which is associated with the upregulation of cyclin B1 and the dephosphorylation of Cdc2. Treatment of K562 and K562R cells with MPT0B206 induced apoptosis and reduced the protein levels of procaspase-9 and procaspase-3 and increased caspase-3 activity and PARP cleavage. MPT0B206 also reduced the levels of the antiapoptotic proteins Mcl-1 and Bcl-2 and increased the level of the apoptotic protein Bax. Additional experiments showed that MPT0B206 markedly downregulated Bcr-Abl mRNA expression and total and phosphorylated Bcr-Abl protein levels and inhibited the phosphorylation of its downstream proteins STAT5, MAPK, and AKT, and the protein level of c-Myc in K562 and K562R cells. Furthermore, MPT0B206 triggered viability reduction and apoptosis in CML cells carrying T315I-mutated Bcr-Abl. Together, these results suggest that MPT0B206 is a promising alternative for treating imatinib-resistant CML.
authors.affiliation: Neurosurgery Department, Chi Mei Medical Center, No. 901, Zhonghua Rd., Tainan, 710, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Chen
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: 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: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Yu-Hsiu
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Chin-Wei
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan.
authors.forename: Tsai-Yun
authors.initials: TY
authors.lastname: Chen
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D058105:Polymerization / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C000626351:N-(1-4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)formamide; D013450:Sulfones; D014404:Tubulin; D050257:Tubulin Modulators; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Apoptosis; Bcr-Abl; G2/M arrest; Imatinib resistance; Tubulin polymerization inhibitor