title: A novel anticancer agent, SKLB70359, inhibits human hepatic carcinoma cells proliferation via G0/G1 cell cycle arrest and apoptosis induction.
abstract: Hepatocellular carcinoma is one of the most common cancers in worldwide. We previously reported a novel thienopyridine derivative 3-amino-6-(3,4-dichlorophenyl) thieno[2,3-b]pyridine-2-carboxamide (SKLB70359) which possesses anticancer activity against hepatocellular carcinoma. In present study, we further investigated its anticancer activity and possible mechanism. The SKLB70359 treatment decreased the viability of a panel of hepatocellular carcinoma cell lines in a concentration- and time-dependent manner with IC(50) 0.4 ~ 2.5 μM. The mechanism study showed that SKLB70359 induced G0/G1 cell cycle arrest and then led to apoptotic cell death of HepG2 cell. The SKLB70359 induced G0/G1 cell cycle arrest was characterized by down-regulation of cyclin-dependent kinase 2 (CDK2), CDK4, CDK6 expression and up-regulation of p53, p21(WAF1). Activating of caspase-3 and caspase-9 was also observed. Meanwhile, proliferation inhibitory effect of SKLB70359 was associated with decreased level of phosphorylated p44/42 mitogen activated protein kinase (p44/42 MAPK) and phosphorylated retinoblastoma protein (Rb). Moreover, SKLB70359 exhibit less toxicity to non-cancer cells than tumor cells. In conclusion, the findings in this study suggested that SKLB70359 have potential anticancer efficacy via G0/G1 cell cycle arrest and apoptosis induction. Its potential to be a candidate of anticancer agent is worth being further investigated.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Dai
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Zeng
authors.forename: Feng
authors.initials: F
authors.lastname: Peng
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Han
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Lin
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Tian
authors.initials: T
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Yi
authors.initials: Y
authors.lastname: Deng
authors.forename: Yong-Qiu
authors.initials: YQ
authors.lastname: Mao
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016160:Retinoblastoma Protein / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C573548:3-amino-6-(3,4-dichlorophenyl)thieno(2,3-b)pyridine-2-carboxamide; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011725:Pyridines; D016160:Retinoblastoma Protein; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D053453:Caspase 9