title: KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL.
abstract: Kinesin spindle protein (KSP) is a microtubule-associated motor protein that is specifically expressed by mitosis cells. It is highly expressed in various types of tumors including hematomalignances and solid tumors. Chemical KSP inhibition has become a novel strategy in the development of anticancer drugs. SB743921 is a selective inhibitor for KSP, which is a mitotic protein essential for cell-cycle progression. Although SB743921 has shown antitumor activities for several types of cancers and entered into clinical trials, its therapeutic effects on breast cancer and mechanisms have not been explored. In this study, we tested the antitumor activity of SB743921 in breast cancer cell lines and partly elucidated its mechanisms. KSP and denticleless E3 ubiquitin-protein ligase homolog (DTL) are overexpressed in breast cancer cells compared with no-cancer tissues. Chemical inhibition of KSP by SB743921 not only reduces proliferation but also induces cell-cycle arrest and leads to apoptosis in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with SB743921 results in decreased ability of colony formation in culture. SB743921 treatment also causes a KSP accumulation in protein level that is associated with cell arrest. Furthermore, we showed that SB743921 treatment significantly reduces the expression of bcl-2 and cell cycle-related protein DTL, and upregulates p53 and caspase-3 in breast cancer cells. Taken together, these data indicated that SB743921 can be expected to be a novel treatment agent for breast cancers.
authors.affiliation: Departments of aBreast and Thyroid Surgery bGeneral Surgery, Changhai Hospital, Second Military Medical University, Shanghai cDepartment of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Fengjun
authors.initials: F
authors.lastname: Xiao
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Huiyan
authors.initials: H
authors.lastname: Sun
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sheng
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: C000595707:BCL2 protein, human; D001549:Benzamides; D002867:Chromones; C429530:DTL protein, human; C470243:KIF11 protein, human; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C557279:SB 743921; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016547:Kinesins