The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines

被引：40

作者：

Gahr, Susanne ^{[1
]}

Peter, Gisela ^{[1
]}

Wissniowski, Thadaus Till ^{[1
]}

Hahn, Eckhart G. ^{[1
]}

Herold, Christoph ^{[1
]}

Ocker, Matthias ^{[1
]}

机构：

[1] Univ Hosp Erlangen, Dept Med 1, D-91054 Erlangen, Germany

来源：

ONCOLOGY REPORTS | 2008年 / 20卷 / 05期

关键词：

hepatocellular carcinoma; CYC-202; MS-275; histone deacetylase inhibitor; CDK inhibitor;

D O I：

10.3892/or_00000137

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Effective therapies for advanced stages of hepatocellular carcinoma (HCC) have yet to be developed. We investigated how far a combination of the HDAC inhibitor MS-275 and the CDK inhibitor CYC-202 synergizes to inhibit proliferation and promotes apoptosis of hepatoma cells in vitro. Human hepatoma cell lines Hep3B and HepG2 as well as primary human foreskin fibroblasts as non-malignant controls were cultured under standardized conditions and incubated with increasing concentrations of CYC-202 and MS-275 as single agents and in combination. After 24 to 72 h, apoptosis was analyzed by flow cytometry (propidium iodide, JC-1) and by immunocytochemistry for cytokeratin 18 fragmentation. DNA synthesis was assessed using bromodeoxyuridine incorporation. Protein was separated for Western blotting against p21, bax and bcl-2 and fluorimetric activity assays against caspase 3 and 8. The results showed that the combination of CYC-202 and MS-275 leads to better proapoptotic effects than the employment of single substances. Apoptosis was induced via the mitochondrial pathway as evidenced by a shift in the bax/bcl-2 ratio and breakdown of mitochondrial transmembrane potentials. Caspase assays revealed a strong induction of caspase 3 but not of the extrinsic initiator caspase 8. In conclusion, combination therapy with the biomodulators MS-275 and CYC-202 is a promising treatment option for HCC.

引用

页码：1249 / 1256

页数：8