title: MPT0G066, a novel anti-mitotic drug, induces JNK-independent mitotic arrest, JNK-mediated apoptosis, and potentiates antineoplastic effect of cisplatin in ovarian cancer.
abstract: Developing new anticancer agents against ovarian cancer is an urgent medical need. MPT0G066, a novel synthetic arylsulfonamide compound, was shown to inhibit cell growth and decrease viability in human ovarian cancer cells. MPT0G066 induced arrest of the cell cycle at the multipolyploidy (MP) phase in SKOV3 and at the G2/M phase in A2780 cells, while increasing the proportion of cells in the subG1. Additionally, MPT0G066 induced c-Jun-NH2 terminal kinase (JNK) activation, influenced cell cycle regulatory and Bcl-2 family proteins, which triggered intrinsic apoptotic pathways through cleavage of caspase-3, -7, -9, and poly-(ADP-ribose) polymerase (PARP). Flow cytometry analysis of p-glycoprotein (p-gp) function showed that MPT0G066 was not a substrate of p-gp. Additionally, it was shown that MPT0G066 could decrease cell viability in multiple-drug-resistant human ovarian cancer cells. Furthermore, the combination of MPT0G066 and cisplatin presented a synergistic cytotoxic effect against ovarian cancer cell lines in vitro. MPT0G066 also significantly suppressed the growth of ovarian carcinoma and potentiated the antineoplastic effects of cisplatin in vivo. In conclusion, these findings indicate that MPT0G066 can be a potential anticancer agent against ovarian cancer that worthy of further development.
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Han-Li
authors.initials: HL
authors.lastname: Huang
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Min-Wu
authors.initials: MW
authors.lastname: Chao
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Li
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Hsun
authors.initials: LH
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Chen
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Chun
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D048670:MAP Kinase Kinase 4; D002945:Cisplatin