title: MPT0B169, a novel tubulin inhibitor, induces apoptosis in taxol-resistant acute myeloid leukemia cells through mitochondrial dysfunction and Mcl-1 downregulation.
abstract: Acute myeloid leukemia (AML) is a hematological malignant disorder. AML cells are not susceptible to chemotherapeutic drugs because of their multidrug resistance (MDR). Antitubulin agents are currently employed in cancer treatments; however, drug resistance results in treatment failures because of MDR1 expressing cancer cells. We previously synthesized a new tubulin inhibitor, 2-dimethylamino-N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-acetamide (MPT0B169), which inhibits AML cell proliferation by arresting cell cycle at the G2/M phase. In this study, we explored the effect of MPT0B169 on apoptosis in AML HL60 and NB4 cells and MDR1-mediated taxol-resistant HL60/TaxR cells and the underlying mechanism. MPT0B169 induced concentration- and time-dependent apoptosis in these cancer cells, as observed through annexin V/propidium iodide double staining and flow cytometry. Furthermore, DNA fragmentation analysis confirmed MPT0B169-induced apoptosis. MPT0B169 induced a loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, cleavage and activation of caspase-9 and caspase-3, and consequently cleavage of poly (ADP ribose) polymerase. Western blot analysis showed that MPT0B169 markedly reduced Mcl-1 (an antiapoptotic protein) levels; however, it caused no changes in Bcl-2 or BAX (a proapoptotic protein). Knockdown of Mcl-1 using small interfering RNA (siRNA) slightly induced growth inhibition and apoptosis in the HL60 and HL60/TaxR cells. Further investigation revealed that Mcl-1 siRNA enhanced the sensitivity of HL60 and HL60/TaxR cells to MPT0B169-induced growth inhibition and apoptosis. Together, these results demonstrated that MPT0B169-induced apoptosis in nonresistant and MDR1-mediated taxol-resistant AML cells through Mcl-1 downregulation and a mitochondria-mediated pathway. MPT0B169 can overcome MDR1-mediated drug resistance in AML cells.
authors.affiliation: Department of Neurosurgery, Chi-Mei Medical Center, No. 901, Zhonghua Rd., Tainan, 710, Taiwan.
authors.forename: Che-Chuan
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Hsinjin Eugene
authors.initials: HE
authors.lastname: Liu
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: Yu-Wen
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan. jpl@tmu.edu.tw.
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. cmbhhm@tmu.edu.tw.
authors.forename: Huei-Mei
authors.initials: HM
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C587776:2-dimethylamino-N-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)acetamide; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D050257:Tubulin Modulators; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel; D012521:Sarcosine
keywords: Acute myeloid leukemia cells; MDR1-mediated resistance; MPT0B169; Mcl-1; Mitochondria-mediated apoptosis; Tubulin inhibitor