(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Carcinoma--Hepatocellular

Usage of statins is suggested to decrease the incidence of HCC. When it comes to different statin subtypes, the chemopreventive action remains controversial. We aim to compare the usage of different statins and reduction of HCC risk.. We searched PubMed, Embase.com and Cochrane Library database up to August 10, 2015. Duplicated or overlapping reports were eliminated. We performed a traditional pair-wise meta-analysis and a Bayesian network meta-analysis to compare different treatments with a random-effects model.. We reviewed five observational studies enrolling a total of 87127 patients who received at least two different treatment strategies including rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, and lovastatin or observation alone. Direct comparisons showed that usage of atorvastatin (OR 0.63, 95%CI 0.45-0.89) and fluvastatin (OR 0.58, 95%CI 0.40-0.85) could significantly cut the risk of liver cancer. The difference of indirect comparisons between the included regimens is not statistically significant. However, usage of all types of statins, such as fluvastatin (RR 0.55, 95%CI 0.26-1.11), atorvastatin (RR 0.59, 95%CI 0.30-1.16), simvastatin (RR 0.69, 95%CI 0.38-1.25), cerivastatin (RR 0.71, 95%CI 0.19-2.70), pravastatin (RR 0.72, 95%CI 0.37-1.45), lovastatin (RR 0.81, 95%CI 0.34-1.96) and rosuvastatin (RR 0.92, 95%CI 0.44-1.80), appeared to be superior to observation alone. Notably, fluvastatin was hierarchically the best when compared with the six other statins.. Our analyses indicate the superiority of usage of statins in reduction of liver cancer. Available evidence supports that fluvastatin is the most effective strategy for reducing HCC risk compared with other statin interventions.

Topics: Atorvastatin; Bayes Theorem; Carcinoma, Hepatocellular; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Liver Neoplasms; Lovastatin; Observational Studies as Topic; Pravastatin; Pyridines; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

Drug resistance to sorafenib is common in patients with hepatocellular carcinoma(HCC). We examined the effects of a combination of sorafenib and fluvastatin on HCC using in vitro and in vivo models. The dual treatment induced apoptosis and reduced cellular viability in HCC more effectively than either drug alone. The combination treatment also inhibited activation of hepatic stellate cells, whereas single drug treatments did not. On a molecular level, combined treatment inhibited activation of the MAPK and NF-κB pathways via Toll-like receptor 4 in HCC cells. Combined treatment also inhibited expression of stromal cell-derived factor 1α in HCC cells, which further inhibited the MAPK pathway in hepatic stellate cells. These results suggest that a combination of sorafenib and fluvastatin may be a promising therapeutic strategy for patients with advanced HCC.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hep G2 Cells; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Rats; Rats, Wistar; Signal Transduction; Sorafenib

Metastasis occurs due to migration of the cells from primary tumor toward other tissues by gaining invasive properties. Since metastatic invasion shows a strong resistance against conventional cancer treatments, the studies on this issue have been focused. Within this context, inhibition of migration and determination of the relationships at the gene level will contribute to treatment of metastatic cancer cases. We have aimed to demonstrate the impact of TGF-β1 and fluvastatin on human breast cancer (MCF-7) and human hepatocellular carcinoma (Hep3B) cell cultures via Real-Time Cell Analyzer (RTCA) and to test the expression levels of some genes (NDRG1, SGK1, TWIST1, AMPKA2) and to compare their gene expression levels according to RTCA results. Both of cell series were applied TGF-β1 and combinations of TGF-β1/fluvastatin. Primer and probes were synthesized using Universal Probe Library (UPL, Roche) software, and expression levels of genes were tested via qPCR using the device LightCycler 480 II (Roche). Consequently, fluvastatin dose-dependently inhibited migration induced by TGF-β1 in both groups. This inhibition was accompanied by low level of SGK1 messenger RNA (mRNA) and high levels of NDRG1 and AMPKA2 mRNA. Thus, we conclude that fluvastatin plays an important role in reducing resistance to chemotherapeutics and preventing metastasis.

Topics: AMP-Activated Protein Kinases; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Movement; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Immediate-Early Proteins; Indoles; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; MCF-7 Cells; Neoplasm Metastasis; Nuclear Proteins; Protein Serine-Threonine Kinases; RNA, Messenger; Transforming Growth Factor beta1; Twist-Related Protein 1

Statins are associated with delayed fibrosis progression and a reduced risk of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV). Limited data exist regarding the most effective type and dose of statin in this population. We sought to determine the impact of statin type and dose upon fibrosis progression and HCC in patients with HCV. Using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified all subjects initiated on HCV antibody (anti-HCV) therapy from 2001 to 2014, and all incident cases of cirrhosis and HCC. Statin use was measured using cumulative defined daily dose (cDDD). Multivariable Cox's proportional hazard regression models were used to examine the relationship between statin use and development of cirrhosis and HCC. Among 9,135 eligible subjects, 1,649 developed cirrhosis and 239 developed incident HCC. Statin use was associated with a 44% reduction in development of cirrhosis (adjusted hazard ratio [HR]: 0.6; 95% confidence interval [CI]: 0.53, 0.68). The adjusted HRs (95% CI) of fibrosis progression with statin cDDD 28-89, 89-180, and >180 were 0.74 (0.59, 0.93), 0.71 (0.59, 0.88), and 0.6 (0.53, 0.68), respectively. Mean change in FIB-4 score with atorvastatin (n = 944) and fluvastatin (n = 34) was -0.17 and -0.13, respectively (P = 0.04), after adjustment for baseline FIB-4 score and established predictors of cirrhosis. Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed.. In patients with chronic HCV, statin use was associated with a dose-dependent reduction in incident cirrhosis and HCC. Atorvastatin and fluvastatin were associated with the most significant antifibrotic effects, compared with other statins. (Hepatology 2016;64:47-57).

Topics: Atorvastatin; Carcinoma, Hepatocellular; Cohort Studies; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fibrosis; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

Mitochondria are semi-autonomous organelles regulated by a complex network of proteins that are vital for many cellular functions. Because mitochondrial modulators can impact many aspects of cellular homeostasis, their identification and validation has proven challenging. It requires the measurement of multiple parameters in parallel to understand the exact nature of the changes induced by such compounds. We developed a platform of assays scoring for mitochondrial function in two complementary models systems, mammalian cells and C. elegans. We first optimized cell culture conditions and established the mitochondrial signature of 1,200 FDA-approved drugs in liver cells. Using cell-based and C. elegans assays, we further defined the metabolic effects of two pharmacological classes that emerged from our hit list, i.e. imidazoles and statins. We found that these two drug classes affect respiration through different and cholesterol-independent mechanisms in both models. Our screening strategy enabled us to unequivocally identify compounds that have toxic or beneficial effects on mitochondrial activity. Furthermore, the cross-species approach provided novel mechanistic insight and allowed early validation of hits that act on mitochondrial function.

Topics: Animals; Caenorhabditis elegans; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cluster Analysis; Drug Approval; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Indoles; Lovastatin; MCF-7 Cells; Mice; Mitochondria; Oxidative Phosphorylation; Oxygen Consumption; Pharmaceutical Preparations; Reproducibility of Results; Simvastatin; United States; United States Food and Drug Administration

Hepatitis C virus (HCV)-induced alterations in lipid metabolism and cellular protein expression contribute to viral pathogenesis. The mechanism of pleiotropic actions of cholesterol-lowering drugs, statins, against HCV and multiple cancers are not well understood. We investigated effects of fluvastatin (FLV) on microtubule-associated and cancer stem cell marker (CSC), doublecortin-like kinase 1 (DCLK1) during HCV-induced hepatocarcinogenesis. HCV replication models, cancer cell lines and normal human hepatocytes were used to investigate the antiviral and antitumor effects of statins. FLV treatment resulted in induction of microtubule bundling, cell-cycle arrest and alterations in cellular DCLK1 distribution in HCV-expressing hepatoma cells. These events adversely affected the survival of liver-derived tumor cells without affecting normal human hepatocytes. FLV downregulated HCV replication in cell culture where the ATP pool and cell viability were not compromised. Pravastatin did not exhibit these effects on HCV replication, microtubules and cancer cells. The levels of miR-122 that regulates liver homeostasis and provides HCV genomic stability remained at steady state whereas DCLK1 mRNA levels were considerably reduced during FLV treatment. We further demonstrated that HCV replication was increased with DCLK1 overexpression. In conclusion, unique effects of FLV on microtubules and their binding partner DCLK1 are likely to contribute to its anti-HCV and antitumor activities in addition to its known inhibitory effects on 3-hydroxy-3-methylglutary-CoA reductase (HMGCR).

Topics: Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Doublecortin-Like Kinases; Down-Regulation; Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatocytes; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Microtubules; Protein Serine-Threonine Kinases; Virus Replication

HMG-CoA-reductase inhibitors (statins) are widely used drugs to interfere with cholesterol biosynthesis. Besides this usage, evidence is increasing that statins might also be useful in therapy of viral infections or cancer. We investigated the effects of fluva-, simva-, atorva-, rosuva- and lovastatin on the viability of primary mouse and human hepatocytes as well as mouse (Hepa1-6) and human (Huh7, HepG2) hepatoma cell lines. Our results show selective cytotoxic effects of fluva-, simva- and lovastatin on hepatoma cells in comparison to primary hepatocytes. Using human hepatoma cells we found significant reduction of cell viability and induction of apoptosis in HepG2 cells, while statins did not affect Huh7 cells at concentrations not toxic for primary hepatocytes. Stable knockdown of endogenous p53, which is overexpressed in Huh7 cells, was able to restore susceptibility of Huh7 cells towards statin-induced toxicity. The anti-tumor effect of statins did not depend on a lack of cholesterol production, but was restored by supplementation of mevalonate or geranyl-geranyl pyrophosphate, prerequisites for prenylation of small G proteins. In conclusion, statins display a selective apoptotic effect on human hepatoma cells, with fluva-, simva- and lovastatin being both, most selective for tumor cells and most effective in inducing tumor cell apoptosis. Additionally, our results implicate that anti-tumor activity of statins requires cell proliferation and is reduced by p53 overexpression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Atorvastatin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Cholesterol; Drug Screening Assays, Antitumor; Fatty Acids, Monounsaturated; Fluorobenzenes; Fluvastatin; Gene Expression; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipid Metabolism; Liver Neoplasms; Lovastatin; Mice; Mice, Inbred C57BL; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Simvastatin; Sulfonamides; Tumor Suppressor Protein p53

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the sterol biosynthesis pathway. Statin therapy is commonly regarded as well tolerated. However, serious adverse effects have also been reported, especially during high-dose statin therapy. The aim of our study was to investigate the effect of statins on gene expression profiles in human hepatoma HepG2 cells using Affymetrix Human Genome U133 Plus 2.0 arrays. Expression of 102, 857 and 1091 genes was changed substantially in HepG2 cells treated with simvastatin, fluvastatin and atorvastatin, respectively. Pathway and gene ontology analysis showed that many of the genes with changed expression levels were involved in a broad range of metabolic processes. The presented data clearly indicate substantial differences between the tested statins.

Topics: Atorvastatin; Carcinoma, Hepatocellular; Computational Biology; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Profiling; Gene Expression Regulation; Genome, Human; Hep G2 Cells; Heptanoic Acids; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Metabolic Networks and Pathways; Mevalonic Acid; Oligonucleotide Array Sequence Analysis; Pilot Projects; Principal Component Analysis; Pyrroles; Simvastatin

To evaluate effects of celecoxib (a selective cox-2 inhibitor)combined with fluvastatin (a HMG-CoA reductase inhibitor) on tumor growth and cell apoptosis in hepatocellular carcinoma xenograft in nude mice.. Hepatocellular carcinoma BEL-7402 cells were inoculated subcutaneously into the left armpit of nude mice, the mice (n = 32) were then randomly divided into 4 groups: the control group, the celecoxib group,the fluvastatin group and the combination group. At the end of the study, Tumor Tissues were collected for analysis. Cell apoptosis was determined by flow cytometry analysis and TUNEL assay. Akt, p-Akt and survivin protein levels were measured by Western blot. Statistical comparisons were made using factorial analysis of variance (ANOVA) and multiple comparisons between each two groups were calculated using SNK-q test.. The combination of Celecoxib and fluvastatin resulted in a greater inhibition of tumor growth than either agent alone, the tumor inhibitory rate was 34.0% in the Celecoxib group, 25.0% in the fluvastatin group and 72.2% in the combination group. The percentages of TUNEL--positive cancer cells in the celecoxib and fluvastatin alone treatment groups were 8.5%+/-1.4% and 9.4%+/-1.7% respectively as compared to the control group which was 3.5%+/-0.8%. Combination therapy showed a significantly greater increase in tumor cell apoptosis in comparison with the control and single-therapy groups (apoptotic index: 19.4%+/-3.0%; P value is less than 0.01 versus celecoxib or fluvastatin groups). The results of flow cytometry analysis also showed the same tendency. a small number of apoptotic cells were detected in the control tumours (4.1%+/-1.6%), whereas a large number of apoptotic cells were detected in tumours treated with celecoxib (9.1%+/-2.1%) or fluvastatin (10.1%+/-2.3%) alone; and the combination therapy resulted in even more apoptotic cells (23.6%+/-5.8%; P value is less than 0.01 versus celecoxib or fluvastatin groups). Western blot analysis demonstrated that the combination of celecoxib and fluvastatin significantly down-regulated p-Akt (0.23+/-0.08 versus 1.12+/-0.07 and surviving (0.50+/-0.07 versus 1.47+/-0.19) in BEL-7402 tumours compared with the control (P value is less than 0.01 for all).. The present study provided evidence that treatment with celecoxib in combination with fluvastatin resulted in the inhibition of HCC tumour growth in an in vivo mouse model.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Celecoxib; Cell Line, Tumor; Cyclooxygenase 2 Inhibitors; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Mice; Mice, Inbred BALB C; Mice, Nude; Pyrazoles; Sulfonamides; Xenograft Model Antitumor Assays

Fluvastatin, a lipophilic statin, was known to inhibit proliferation and induce apoptosis in many cancer cells. Its potential anticancer was evaluated in three hepatocellular carcinoma (HCC) cell lines (HepG2, SMMC-7721 and MHCC-97H). Cells were treated with fluvastatin in vitro and its effect on cell proliferation, cell cycle, invasion and apoptosis was determined. Mechanism of apoptosis induced by fluvastatin on HCC cell lines was also investigated through western blotting and mitochondrial membrane potential (MMP) analysis. It was observed that fluvastatin inhibited proliferation of HCC cells by inducing apoptosis and G2/M phase arrest in a dose-dependent manner. The results of cell invasion assay revealed that fluvastatin significantly decreased the invasion potency of HCC cells. A mitochondria-operated mechanism for fluvastatin induced apoptosis might be involved and was supported by Western blotting and MMP analysis. After fluvastatin treatment, expression of Bcl-2 and procaspase-9 were downregulated, cytochrome c (cytosolic extract), Bax and cleaved-caspase-3 protein expression were increased. Furthermore, a breakdown of MMP in HCC cells was observed. To conclude, these results have provided a rationale for clinical investigations of fluvastatin in future as a potential anticancer reagent for growth control of HCC.

Topics: Anticholesteremic Agents; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Caspase 3; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Cytochromes c; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Liver Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Tumor Cells, Cultured

CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.

Topics: Animals; Atorvastatin; Carcinoma, Hepatocellular; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fibroblasts; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver Neoplasms; Lovastatin; Male; Naphthalenes; Pravastatin; Pyrroles; Rats; Rats, Inbred Strains; Sterols; Tetrazoles; Tumor Cells, Cultured