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: Xiao-Yun Dai, Xiu-Xiu Zeng, Feng Peng, Yuan-Yuan Han, Hong-Jun Lin, You-Zhi Xu, Tian Zhou, Gang Xie, Yi Deng, Yong-Qiu Mao, Luo-Ting Yu, Li Yang, Ying-Lan Zhao
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 29 Issue 1-2 Pg. 281-90 ( 2012) ISSN: 1421-9778 [Electronic] Germany
• PMID: 22415097 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 S. Karger AG, Basel.

Chemical References

• 3-amino-6-(3,4-dichlorophenyl)thieno(2,3-b)pyridine-2-carboxamide
• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Pyridines
• Retinoblastoma Protein
• Thiophenes
• Tumor Suppressor Protein p53
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Caspase 3
• Caspase 9

Topics

• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase 4 (metabolism)
• Cyclin-Dependent Kinase 6 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Drug Screening Assays, Antitumor
• G1 Phase Cell Cycle Checkpoints (drug effects)
• HCT116 Cells
• HEK293 Cells
• HeLa Cells
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• Pyridines (chemistry, pharmacology, therapeutic use)
• Retinoblastoma Protein (metabolism)
• Thiophenes (chemistry, pharmacology, therapeutic use)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation