title: SKLB70326, a novel small-molecule inhibitor of cell-cycle progression, induces G₀/G₁ phase arrest and apoptosis in human hepatic carcinoma cells.
abstract: We previously reported the potential of a novel small molecule 3-amino-6-(3-methoxyphenyl)thieno[2.3-b]pyridine-2-carboxamide (SKLB70326) as an anticancer agent. In the present study, we investigated the anticancer effects and possible mechanisms of SKLB70326 in vitro. We found that SKLB70326 treatment significantly inhibited human hepatic carcinoma cell proliferation in vitro, and the HepG2 cell line was the most sensitive to its treatment. The inhibition of cell proliferation correlated with G(0)/G(1) phase arrest, which was followed by apoptotic cell death. The SKLB70326-mediated cell-cycle arrest was associated with the downregulation of cyclin-dependent kinase (CDK) 2, CDK4 and CDK6 but not cyclin D1 or cyclin E. The phosphorylation of the retinoblastoma protein (Rb) was also observed. SKLB70326 treatment induced apoptotic cell death via the activation of PARP, caspase-3, caspase-9 and Bax as well as the downregulation of Bcl-2. The expression levels of p53 and p21 were also induced by SKLB70326 treatment. Moreover, SKLB70326 treatment was well tolerated. In conclusion, SKLB70326, a novel cell-cycle inhibitor, notably inhibits HepG2 cell proliferation through the induction of G(0)/G(1) phase arrest and subsequent apoptosis. Its potential as a candidate anticancer agent warrants further investigation.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Han
authors.forename: Haiyun
authors.initials: H
authors.lastname: He
authors.forename: Feng
authors.initials: F
authors.lastname: Peng
authors.forename: Jiyan
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dai
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lin
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Xu
authors.forename: Tian
authors.initials: T
authors.lastname: Zhou
authors.forename: Yongqiu
authors.initials: Y
authors.lastname: Mao
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C574230:3-amino-6-(3-methoxyphenyl)thieno(2.3-b)pyridine-2-carboxamide; D000970:Antineoplastic Agents; D011725:Pyridines; D013876:Thiophenes