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.
Copyright © 2012 S. Karger AG, Basel.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Drug Screening Assays, Antitumor
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G1 Phase Cell Cycle Checkpoints / drug effects*
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HCT116 Cells
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Phosphorylation
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Pyridines / chemistry
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Pyridines / pharmacology*
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Pyridines / therapeutic use
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Retinoblastoma Protein / metabolism
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Thiophenes / chemistry
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Thiophenes / pharmacology*
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Thiophenes / therapeutic use
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation
Substances
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3-amino-6-(3,4-dichlorophenyl)thieno(2,3-b)pyridine-2-carboxamide
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Antineoplastic Agents
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Cyclin-Dependent Kinase Inhibitor p21
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Pyridines
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Retinoblastoma Protein
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Thiophenes
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Tumor Suppressor Protein p53
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Caspase 3
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Caspase 9