Cardiotonic steroids attenuate ERK phosphorylation and generate cell cycle arrest to block human hepatoma cell growth
| Autor: | Xia Mai, Ga-Hu Zala, Shi-Xiang Cheng, Rui-Cheng Xu, Mo-Jie Gao, Wen-Liang Hu, Zhong-Wei Xu, Nana Shan, Xiao-Yi Chen, Fengmei Wang |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Cyclin-Dependent Kinase Inhibitor p21 Cell cycle checkpoint Carcinoma Hepatocellular Cell Survival Endocrinology Diabetes and Metabolism Clinical Biochemistry Cyclin A Blotting Western Apoptosis Pharmacology Biochemistry Ouabain Endocrinology Cyclin-dependent kinase Cell Line Tumor Proliferating Cell Nuclear Antigen medicine Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Molecular Biology Cell Proliferation Microscopy Confocal biology Cell growth Reverse Transcriptase Polymerase Chain Reaction Cyclin-dependent kinase 2 Cell Cycle Cyclin-Dependent Kinase 2 Cell Biology Hep G2 Cells Cell cycle Molecular biology Bufanolides biology.protein Molecular Medicine Calcium medicine.drug |
| Zdroj: | The Journal of steroid biochemistry and molecular biology. 125(3-5) |
| ISSN: | 1879-1220 |
| Popis: | Recent studies revealed the potential of Na(+)/K(+)-ATPase as a target for anticancer therapy and showed additional modes of action of cardiotonic steroids (CSs), a diverse family of naturally derived compounds, as inhibitors of Na(+)/K(+)-ATPase. The results from epidemiological studies showed significantly lower mortality rates in cancer patients receiving CSs, which sparked interest in the anticancer properties of these drugs. The present study was designed to investigate the anticancer effect of CSs (ouabain or cinobufagin) and to elucidate the molecular mechanisms of CS activity in hepatoma cell lines (HepG2 and SMMC-7721). Ouabain and cinobufagin significantly inhibited cell proliferation by attenuating the phosphorylation of extracellular regulated kinase (ERK) and down-regulating the expression of C-myc. These CSs also induced cell apoptosis by increasing the concentration of intracellular free calcium ([Ca(2+)](i)) and induced S phase cell cycle arrest by down-regulating the expression of Cyclin A, cyclin dependent kinase 2 (CDK2) and proliferating cell nuclear antigen (PCNA) as well as up-regulating the expression of cyclin dependent kinase inhibitor 1A (p21(CIP1)). Overexpression of ERK reversed the antiproliferation effect of ouabain or cinobufagin in HepG2 and SMMC-7721 cells. Currently, the first generation of CS-based anticancer drugs (UNBS1450 and Anvirzel) are in Phase I clinical trials. These data clearly support their potential use as cancer therapies. |
| Databáze: | OpenAIRE |
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