Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor

Sutter, Andreas; Maaser, Kerstin; Höpfner, Michael; Huether, Alexander; Schuppan, Detlef; Scherübl, Hans

doi:10.1016/j.jhep.2005.04.010

Cited by 81 publications

(62 citation statements)

References 52 publications

(65 reference statements)

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“…In particular, lipid soluble statins have been also shown to produce antitumor effects, and reduce intracellular cholesterol level. [22][23][24] In the present study, single treatment of lovastatin showed weak anticancer cell cytotoxicity. Moreover, the micromolar concentration of diazepam-and flavonoids-induced cytotoxic activity in the cancer cells in this study was not reduced by the addition of 5-fluorouracil (5-FU), a chemotherapeutic agent.…”

Section: Discussionsupporting

confidence: 47%

Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Kim

Lee

et al. 2008

Biological & Pharmaceutical Bulletin

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Section: Discussionsupporting

confidence: 47%

Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Kim

Lee

et al. 2008

Biological & Pharmaceutical Bulletin

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“…However, it was recently reported that statins inhibited the proliferation of hepatocellular carcinoma cell lines (HuH-7 and HepG2) by inducing apoptosis and G1/S cell-cycle arrest. 22 Because that study found the IC 50 of FLV in HuH-7 cells to be 10 Ϯ 3 mol/L, we further examined the effects of FLV on the proliferation of OR6 cells by varying the concentration (up to 10 mol/L) of FLV.…”

Section: Inhibition Of Hcv Rna Replication By Statinsmentioning

confidence: 99%

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

et al. 2006

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We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A ( P ersistent hepatitis C virus (HCV) infection causes liver fibrosis and hepatocellular carcinoma. Approximately 170 million people worldwide are infected with HCV. The combination of pegylated interferon (IFN) with ribavirin is the current standard therapy for chronic hepatitis C (CHC) and yields a sustained virological response (SVR) rate of about 55%. 1 This means that about 45% of patients with CH C are still threatened by the progression of the disease to cirrhosis and hepatocellular carcinoma. Until 1999, when Lohmann et al. developed the subgenomic replicon of HCV, it was difficult to screen anti-HCV reagents. 2 Many improvements followed that breakthrough, such as a genome-length HCV RNA replication system 3,4 and a subgenomic replicon with a reporter assay system 5 ; more recently, Wakita et al. used a genotype 2a strain, JFH1, to produce the infectious virus in cell culture. [6][7][8] Genotype 1 is the major genotype of HCV found in Japan, the United States, and many other countries. Unfortunately, the SVR rate after combination therapy of pegylated IFN with ribavirin is less than 50% for this genotype. To find a more effective therapy especially for CHC patients with genotype 1, we recently developed a genome-length HCV RNA (strain O of genotype 1b) replication reporter system (OR6), which has been an effective screening tool. 9,10 Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are in wide use for the treatment of hypercholesterolemia. Recently, it

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“…Furthermore, caspase-3 expression was detected in several human malignancies such as non-small cell lung carcinoma and gastric cancer (7,8). Statins have been proposed as promising adjunctive anti-cancer agents to treat HCC, but their mode of action is still poorly characterized (9). Pitavastatin is a novel highly potent inhibitor of HMG-CoA reductase, the ratelimiting enzyme in cholesterol biosynthesis (10).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of survivin expression and elevation of caspase-3 activity involved in pitavastatin-induced HepG 2 cell apoptosis

Wang¹,

Xu²,

Zhang³

2007

Oncol Rep

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Abstract. The aim of the present study was to research the apoptosis of human hepatocellular carcinoma cell line HepG 2 induced by pitavastatin. HepG 2 cells were treated with increasing doses of pitavastatin or with mevalonic acid for 48 h. The proliferation of cells was detected with WST-8. The morphology of the nucleus was observed under a microscope by Hoechst 33258 staining. The apoptosis peaks were examined by flow cytometry. The expression of survivin mRNA was examined with RT-PCR. The caspase-3 activity was detected with caspase-3 colorimetric protease assay. We found that growth inhibitory effects were observed for treatment with pitavastatin at 10-50 μM. Pitavastatin at 10 μM induced granular apoptotic bodies of HepG 2 cells. Furthermore, pitavastatin at 10 μM increased the appearance of sub-G1 population of HepG 2 cells. Finally, pitavastatin at 10 μM downregulated the expression of survivin mRNA and upregulated the caspase-3 activity, which was clearly related to the HMG-CoA reductase activity. These results suggest that pitavastatin at 10 μM induces apoptosis of HepG 2 cells, which is associated with the decreased expression of survivin mRNA and increased caspase-3 activity of HepG 2 cells.

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Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor

Cited by 81 publications

References 52 publications

Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

Downregulation of survivin expression and elevation of caspase-3 activity involved in pitavastatin-induced HepG 2 cell apoptosis

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