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Pathology Oncology Research : POR Jul 2018Our study aimed to identify key genes involved in the use of fluvastatin and zoledronate against breast cancer, as well as to investigate the roles of vascular...
Our study aimed to identify key genes involved in the use of fluvastatin and zoledronate against breast cancer, as well as to investigate the roles of vascular endothelial growth factor A (VEGFA) in the malignant behaviors of breast cancer cells. The expression data GSE33552 was downloaded from Gene Expression Omnibus database, including mocked-, fluvastatin- and zoledronate-treated MDA-MB-231 cells. Differentially expressed genes (DEGs) were identified in fluvastatin- and zoledronate-treated cells using limma package, respectively. Pathway enrichment analysis and protein-protein interaction (PPI) network analysis were then performed. Then we used shRNA specifically targeting VEGFA (shVEGFA) to knock down the expression of VEGFA in MDA-MB-231 cells. Cell viability assay, scratch wound healing assay, Transwell invasion assay and flow cytometry were performed to explore the effects of VEGFA knockdown on the malignant behaviors of breast cancer cells. VEGFA was up-regulated in both fluvastatin- and zoledronate-treated breast cancer cells. Moreover, VEGFA was a hub node in PPI network. In addition, VEGFA was successfully knocked down in MDA-MB-231 cells by shVEGFA. Suppression of VEGFA promoted the migration and invasion of breast cancer MDA-MB-231 cells. Suppression of VEGFA inhibited the apoptosis of MDA-MB-231 cells. Our results indicate that up-regulation of VEGFA may prevent the progression of breast cancer after fluvastatin and zoledronate treatment via inducing cell apoptosis and inhibiting migration and invasion. VEGFA may serve as a potential prognostic indicator for clinical outcome in the management of breast cancer.
Topics: Anticholesteremic Agents; Apoptosis; Biomarkers, Tumor; Bone Density Conservation Agents; Breast Neoplasms; Cell Movement; Cell Proliferation; Diphosphonates; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Imidazoles; Indoles; Protein Interaction Maps; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Zoledronic Acid
PubMed: 28744693
DOI: 10.1007/s12253-017-0277-4 -
Biological & Pharmaceutical Bulletin 2017Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4...
Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations.
Topics: Area Under Curve; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Mutation
PubMed: 28674251
DOI: 10.1248/bpb.b17-00150 -
Pharmaceutics Mar 2022The purpose of the present research work was to design, optimize, and evaluate fluvastatin-loaded solid lipid nanoparticles (FLV-SLNPs) using 3 factorial design for...
The purpose of the present research work was to design, optimize, and evaluate fluvastatin-loaded solid lipid nanoparticles (FLV-SLNPs) using 3 factorial design for enhancing the bioavailability. Fluvastatin has several disadvantages, including the low solubility and substantial first-pass metabolism resulting in a low (30%) bioavailability and a short elimination half-life. FLV-SLNPs were prepared using the nano-emulsion technique. For the optimization of the FLV-SLNPs, a total of nine formulations were prepared by varying two independent factors at three levels, using full factorial design. In this design, lipid (A) and surfactant (B) concentrations were chosen as independent factors, whereas entrapment efficiency (Y1) and in-vitro drug release (Y2) were selected as the dependent variables. Additionally, the prepared SLNPs were characterized for X-ray diffraction, Fourier transform-infrared spectroscopy, and differential scanning calorimetry. These studies revealed that there were no interactions between the drug and the selected excipients and the selected formulation components are compatible with the drug. Pharmacokinetic studies in rats confirmed significant improvement in AUC and MRT of SLNPs in comparison with the pure drug indicating the enhanced bioavailability of SLNPs. This study provides a proof-of-concept for the fact that SLNPs can be effectively developed via experimental factorial design, which requires relatively minimal experimentation.
PubMed: 35335960
DOI: 10.3390/pharmaceutics14030584 -
Acta Pharmacologica Sinica Oct 2011To investigate whether the combination of fluvastatin and losartan synergistically relieve atherosclerosis and plaque inflammation induced by a high-cholesterol diet in...
AIM
To investigate whether the combination of fluvastatin and losartan synergistically relieve atherosclerosis and plaque inflammation induced by a high-cholesterol diet in rabbits.
METHODS
Atherosclerosis was induced with a high-cholesterol diet for 3 months in 36 New Zealand white rabbits. The animals were randomly divided into model group, fluvastatin (10 mg·kg(-1)·d(-1)) group, losartan (25 mg·kg(-1)·d(-1)) group, and fluvastatin plus losartan group. After the 16-week treatments, the blood samples the animals were collected, and the thoracic aortas were examined immunohistochemically. The mRNA and protein expression levels of monocyte chemotactic protein-1 (MCP-1) were measured using RT-PCR and Western blot.
RESULTS
Compared to the treatment with losartan or fluvastatin alone, the combined treatment did not produce higher efficacy in reduction of blood cholesterol level. However, the combination did synergistically decrease the intimal and media thickness of thoracic aortas with significantly reduced macrophage infiltration and MCP-1 expression in the plaques.
CONCLUSION
The combined treatment with losartan and fluvastatin significantly inhibited atherosclerotic progress and reduced inflammation associated with atherosclerotic plaques.
Topics: Animals; Atherosclerosis; Chemokine CCL2; Cholesterol; Drug Synergism; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Regulation; Indoles; Inflammation; Losartan; Macrophages; Plaque, Atherosclerotic; Rabbits; p38 Mitogen-Activated Protein Kinases
PubMed: 21909126
DOI: 10.1038/aps.2011.95 -
Journal of Family & Reproductive Health Dec 2016To review the potential role and specific impact of statin drugs in women with PCOS. The evidence for this use of statins in PCOS is limited and still under further... (Review)
Review
To review the potential role and specific impact of statin drugs in women with PCOS. The evidence for this use of statins in PCOS is limited and still under further investigation. A search was conducted using PubMed, DynaMed and PubMedHealth databases through October 16, 2016 using the terms . English-language trials evaluating statins in PCOS were obtained and incorporated if they provided relevant data for providers. We summarize twelve trials involving statins in PCOS. The trials were predominantly 12 weeks to 3 months in length (8 of the 12 trials) and low to moderate dose of statin drugs were used. The majority (10 of 12) of the trials show that statins reduce testosterone levels or other androgen hormones (DHEA-S and androstenedione), half of the trials evaluating LH/FSH ratio show an improvement, and all had positive effects on lipid profiles. Statins show promising improvements in serum levels of androgens and LH/FSH ratios translating to improved cardiovascular risk factors above and beyond simply lowering LDL levels. More investigation is needed to determine if statins can clinically impact women with PCOS long term, particularly those who are young and are not yet candidates for traditional preventative treatment with a statin medication.
PubMed: 28546815
DOI: No ID Found -
The Journal of Pharmacology and... Jul 2020Statin drugs are widely employed in the clinic to reduce serum cholesterol. Because of their hydroxymethylglutaryl coenzyme A reductase antagonism, statins also reduce...
Statin drugs are widely employed in the clinic to reduce serum cholesterol. Because of their hydroxymethylglutaryl coenzyme A reductase antagonism, statins also reduce isoprenyl lipids necessary for the membrane anchorage and signaling of small G-proteins in the Ras superfamily. We previously found that statins suppress immunoglobulin E (IgE)-mediated mast cell activation, suggesting these drugs might be useful in treating allergic disease. Although IgE-induced function is critical to allergic inflammation, mast cell proliferation and survival also impact atopic disease and mast cell neoplasia. In this study, we describe fluvastatin-mediated apoptosis in primary and transformed mast cells. An IC was achieved between 0.8 and 3.5 μM in both cell types, concentrations similar to the reported fluvastatin serum C value. Apoptosis was correlated with reduced stem cell factor (SCF)-mediated signal transduction, mitochondrial dysfunction, and caspase activation. Complementing these data, we found that p53 deficiency or Bcl-2 overexpression reduced fluvastatin-induced apoptosis. We also noted evidence of cytoprotective autophagy in primary mast cells treated with fluvastatin. Finally, we found that intraperitoneal fluvastatin treatment reduced peritoneal mast cell numbers These findings offer insight into the mechanisms of mast cell survival and support the possible utility of statins in mast cell-associated allergic and neoplastic diseases. SIGNIFICANCE STATEMENT: Fluvastatin, a statin drug used to lower cholesterol, induces apoptosis in primary and transformed mast cells by antagonizing protein isoprenylation, effectively inhibiting stem cell factor (SCF)-induced survival signals. This drug may be an effective means of suppressing mast cell survival.
Topics: Animals; Apoptosis; Bone Marrow Cells; Cell Line; Cell Survival; Fluvastatin; Humans; Lipid Metabolism; Mast Cells; Mice
PubMed: 32434944
DOI: 10.1124/jpet.119.264234 -
BMC Pharmacology & Toxicology Aug 2022Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming...
BACKGROUND
Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-β (TGFβ) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs).
METHODS
The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student's t-test or the Tukey-Kramer test.
RESULTS
Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin.
CONCLUSIONS
Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.
Topics: Bone Morphogenetic Protein 2; Cell Differentiation; Cells, Cultured; Chondrogenesis; Fluvastatin; Humans; Mesenchymal Stem Cells
PubMed: 35945639
DOI: 10.1186/s40360-022-00600-7 -
Human & Experimental Toxicology 2022The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be...
The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.
Topics: Animals; Coenzyme A; Drug Resistance, Neoplasm; Fatty Acids, Monounsaturated; Fluvastatin; Glioblastoma; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Irinotecan; Mice; Oxidoreductases; Protein Prenylation; Temozolomide
PubMed: 36171180
DOI: 10.1177/09603271221125934 -
Oncotarget Apr 2016Usage 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... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 26943041
DOI: 10.18632/oncotarget.7832 -
Journal of Immunology (Baltimore, Md. :... Feb 2016Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite...
Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune-modulating activities. We tested the in vitro and in vivo effects of statins on IgE-mediated MC and basophil activation. Fluvastatin showed the most significant inhibitory effects of the six statins tested, suppressing IgE-induced cytokine secretion among mouse MCs and basophils. The effects of fluvastatin were reversed by mevalonic acid or geranylgeranyl pyrophosphatase, and mimicked by geranylgeranyl transferase inhibition. Fluvastatin selectively suppressed key FcεRI signaling pathways, including Akt and ERK. Although MCs and basophils from the C57BL/6J mouse strain were responsive to fluvastatin, those from 129/SvImJ mice were completely resistant. Resistance correlated with fluvastatin-induced upregulation of the statin target HMG-CoA reductase. Human MC cultures from eight donors showed a wide range of fluvastatin responsiveness. These data demonstrate that fluvastatin is a potent suppressor of IgE-mediated MC activation, acting at least partly via blockade of geranyl lipid production downstream of HMG-CoA reductase. Importantly, consideration of statin use for treating MC-associated disease needs to incorporate genetic background effects, which can yield drug resistance.
Topics: Acyl Coenzyme A; Animals; Apoptosis; Basophils; Cells, Cultured; Cytokines; Farnesyltranstransferase; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoglobulin E; Indoles; Mast Cells; Mevalonic Acid; Mice; Mice, Inbred C57BL; Signal Transduction; Th2 Cells
PubMed: 26773154
DOI: 10.4049/jimmunol.1501932