Combination Of Simvastatin Research Articles

Beetroot (Beta vulgaris L.) Extract Gives Superior Effect than Beetroot Juice on Increasing HDL and Decreasing LDL and IL-6 in Dyslipidemic Rats Model

BACKGROUND: Dyslipidemia derives from disturbances in lipid metabolism as an interaction between genetic and environmental factors, characterized by increased levels of cholesterol, triglycerides, low-density lipoprotein (LDL) and decreased levels of high-density lipoprotein (HDL). Continuous dyslipidemia will increase the risk of atherosclerosis. In dyslipidemia, macrophages release inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-12, IL-15, IL-18, and then induce T-cell infiltration formed atherosclerotic plaques. Beet (Beta vulgaris L.) which contains active compounds and antioxidant, such as flavonoids and betacyanin, has the ability to reduce dyslipidemia. This study evaluated effect of beetroot juice and beetroot extract on dyslipidemic rat models by evaluating the level of HDL, LDL and IL-6.METHODS: Fourty-two male Sprague Dawley rats were divided into seven groups. Rats were fed either with standard food or high fat diet (HFD) for 28 days, then different interventions using either single combination of simvastatin, beetroot juice, or beetroot extract were given alongside the standard food or HFD diet for another 28 days. LDL and HDL were measured pre- and post-intervention, while IL-6 was measured only post-treatment.RESULTS: Daily administration of a single beetroot juice or beetroot extract or in combination with simvastatin reduced LDL significantly compared to pre-intervention. The interventions also increased HDL significantly and lower IL-6 concentrations compared to group that received no intervention.CONCLUSION: Administration of beetroot juice and beetroot extract can lower LDL, increase HDL, and decrease IL-6 either alone or in combination treatment with simvastatin, it is indicated beetroot have a potential benefit for prevention and therapeutic in dyslipidemia.KEYWORDS: beetroot juice, beetroot extract, LDL, HDL, IL-6

KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment

BackgroundThe KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid–base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions.MethodsWe used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16+/− and KCNJ16−/−) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air–liquid interface.ResultsKCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16−/− organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16−/− kidney organoids.ConclusionsMature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney.

Drug-drug interactions between pemafibrate and statins on pharmacokinetics in healthy male volunteers: Open-label, randomized, 6-sequence, 3-period crossover studies.

Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers.

Pharmacokinetics and Bioequivalence of Fixed-Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open-Label Study in Healthy Volunteers.

The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20mg of simvastatin and 10mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.

Abstract PO4-20-04: A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Abstract Hormone receptor positive (HR+), HER2 negative (HER2-) breast cancers are poor responders to immunotherapy. There is a need for innovative approaches to improve immune responses in these tumors. The combination of statins and aromatase inhibitors have demonstrated antiproliferative and immunomodulatory properties. However, this combination has never been studied in the preoperative setting; thus, our ongoing study represents an opportunity to investigate this approach. We designed a randomized two-arm presurgical “window of opportunity” trial to evaluate the effects of letrozole and simvastatin versus letrozole alone 14 days prior to surgery. Tissue and blood will be obtained at baseline and 14 days after completion of therapy at the time of surgery. Inflammatory markers in the blood and multiplex immunohistochemistry (IHC) in tissue will be assessed. To be eligible for the trial, participants must be postmenopausal women with histologically confirmed stage I-III HR+, HER2- invasive breast cancer with baseline ki-67 ≥10% that have not received prior chemotherapy, endocrine therapy, and/or immunotherapy within 3 months prior to trial enrollment. They should also not have received any cholesterol lowering medication within 3 months prior to trial enrollment. The primary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease in geometric mean % change in ki-67 from pre-surgical baseline to 14 days following preoperative therapy. Ki-67 is a validated surrogate marker for disease-free survival in HR+, HER2- breast cancer. The main secondary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment based on the evaluation of the immune subtype composition in tissue via multiplex immunofluorescence. We aim to enroll 16 patients in each arm to achieve 90% power and detect a minimum difference of 7.5% in ki-67 using a two-sided Mann-Whitney U or Wilcoxon Rank-Sum test. After accounting for a possible drop off rate of 20%, the study’s target accrual will be 40 participants. Statistical analyses will be performed using SAS 9.4. the significance level will be set at alpha = 0.1. Descriptive statistics will be applied to tissue and blood biomarkers of interest at 2 designated time points, prior to preoperative therapy and following completion of preoperative therapy. The absolute change or percentage change of those biomarkers will also be calculated and compared between the 2 arms using the nonparametric Mann-Whitney U test. The correlation among biomarkers will be described by Pearson correlation coefficient with 95% confidence interval. The p-value will be adjusted by Benjamini-Hochberg procedure to control the false discovery rate. All adverse events experienced data will be described by summary statistics and will be assessed according to CTCAE version 5.0. Currently, the study has accrued 2 participants. After completing accrual, we will assess whether the tumor-immune milieu has undergone modulation, resulting in a more immunogenic environment. If an immunogenic effect is demonstrated, this will provide rationale for a future multi-center trial assessing the combination of letrozole, simvastatin, and immunotherapy. Citation Format: Ruth Sacks, Elizabeth Haas, Jade Jones, Manali Bhave, Keerthi Gogineni, Jane Meisel, Demetria Smith-Graziani, Suchi Pakkala, Sarah Friend, Cletus Arciero, Lauren Postlewait, Clara Farley, Cathy Graham, Toncred Styblo, Monica Rizzo, Rhonda Pickett, Nicholas Crasta, Lori Brown, Xiaoxian Li, Sunil Badve, Madhav Dhodapkar, Kevin Kalinsky. A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-04.

Abstract 2038: Statin Targeted Treatment Against Intimal Hyperplasia Using Unique Chitosan-PLGA Nanoparticles

Introduction: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH) after intervention for peripheral arterial disease. Using a unique nanoparticle (NP) to locally maximize statin’s pleiotropic benefits, we hypothesized chitosan-functionalized polylactic-co-glycolic nanoparticles loaded with simvastatin (SL-cNPs) would: 1) be taken up by endothelial cells (ECs) and vascular smooth muscle cells (VSMCs); 2) affect EC and VSMC function; and 3) reduce IH compared to systemic simvastatin. Methods: cNPs were loaded with simvastatin (2% w/w ) and encapsulated with lipophilic tracer, DiD. In vitro , human aortic ECs and VSMCs (passage 3-5) were cultured with 0.2mg SL-cNPs or basal media (30 min). After 24 hours, uptake of SL-cNPs was assessed by immunostaining and flow cytometry. Functional effect of SL-cNPs was determined using qPCR for mRNA expression of RhoA, RhoB and Ras. In vivo, male Sprague-Dawley rats (n=6-9/group) underwent carotid artery balloon injury in the following groups: 1) intraluminal therapy using normal saline control, empty cNPs or SL-cNPs; and 2) oral simvastatin (10mg/kg/day, 7 days pre-operative until sacrifice) plus intraluminal saline or SL-cNPs. Rats were sacrificed (day 14), perfusion fixed, arteries harvested, and IH quantified with morphometric analysis. Student’s t-test and one-way ANOVA was performed (p <0.05 for significance). Results: In vitro , SL-cNPs were readily taken up by ECs (79.6%, 38,606/48,501) and VSMCs (46.4%, 25,774/55,549). SL-cNPs induced a compensatory increase in expression of EC RhoA (1.3-fold) and VSMC RhoA (1.7-fold) and RhoB (5.4-fold) (p<0.05). In vivo, oral simvastatin plus intraluminal SL-cNPs reduced IH compared to controls (0.44 ± 0.04 vs 0.34 ± 0.03, p<0.05). Although oral simvastatin and SL-cNPs alone trended toward IH reduction, the effect was not significant (0.35 ± 0.03 and 0.377 ± 0.03, respectively). No difference existed between oral simvastatin and SL-cNP therapy. Conclusion: cNPs can be used as a novel vehicle to locally deliver statins to vascular cells. Although only the combination of oral simvastatin and SL-cNPs effectively reduced IH, different routes and/or concentration of SL-cNPs may allow for a more robust effect on IH prevention.

Statement of Retraction: Long-term effects of combined simvastatin and metformin treatment on the clinical abnormalities and ovulation dysfunction in single young women with polycystic ovary syndrome

Statement of Retraction: Long-term effects of combined simvastatin and metformin treatment on the clinical abnormalities and ovulation dysfunction in single young women with polycystic ovary syndrome

Long-term hemodynamic response of carvedilol and simvastatin in compensated versus decompensated chronic liver disease with portal hypertension

Background: A combination of carvedilol and Simvastatin have recognized their role as rescue therapy for carvedilol non-responders in chronic liver disease (CLD)-associated portal hypertension. However, there are scarce data regarding its role in specific subclasses, and stratification of response according to the computed tomographic perfusion (CTP) score has never been seen before. Aims and Objective: (1) To compare hemodynamic response and side effects of a combination therapy in decompensated and compensated patients. (2) Stratify the effect of combination therapy according to CTP score. Materials and Methods: In 102 consecutive patients of CLD with esophageal varices, the hepatic venous pressure gradient was measured at baseline and after 3 months of dose optimization of carvedilol. Simvastatin was added to non-responders and hemodynamics repeated at 1 month of dual therapy. The response of compensated CLD was compared with decompensated patients and was stratified as per the CTP on follow-up. Results: Overall, out of 43 compensated patients, 21 responded acutely and response increased to 29 (67.44%) at 3 months. While 31 of 59 (52.54%) decompensated patients responded acutely but dose escalation did not increase response significantly after 3 months. The addition of Simvastatin did increase the response, although side effects were more in decompensated group. The addition of Simvastatin also decreased decompensation in the high-risk compensated group and maintained their MELD.Na. Conclusion: Response in compensated CLD patients was more than in decompensated patients; however, it was statistically insignificant. Attrition was more in patients with CTP >10 due to drug intolerance, side effects, or deaths.

Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models.

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3β1, αvβ3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

Therapeutic potential of Simvastatin and Doxycycline combination for Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder resulting from Amyloid β (Aβ) accumulation. It leads to a decrease in memory and an increase in the production of reactive oxygen species and reactive nitrogen species and also increases Tubulin-associated unit phosphorylation. During AD, the cholesterol levels in the brain increase, and these regions are called lipid rafts. These lipid rafts are hosts for β and γ secretases. As a result, mono fibrils develop, which leads to Aβ oligomerization and, eventually, Aβ accumulation. Hence, the present study was designed to evaluate the protective effect of Simvastatin (cholesterol synthesis inhibitor) and Doxycycline (anti-amyloidogenic drug) for Aβ clearance in an Aβ-induced AD model, in female C57BL/6 mice. The mice were evaluated for spatial memory and olfactory sensation using the Morris water maze and Buried pellet test, respectively. The group treated with the combination of Simvastatin and Doxycycline at two different concentrations showed a recovery of memory and olfactory sensation when compared to the control group. The results have shown that the high-dose combination of Simvastatin and Doxycycline exhibits cholesterol lowering property by blocking the 3-hydroxy-3-methylglutaryl coenzyme A reductase pathway, thereby regulating cholesterol, and eventually resulting in anti-Alzheimer’s activity.

Simvastatin Enhances the Radiosensitivity of Androgen-independent Prostate Cancer Cells via Inhibition of RAD51 Expression.

Statins exert antitumor effects via various mechanisms. Additionally, the recurrence rate of prostate cancer after radiation therapy is lower in patients taking statins. This study investigated the efficacy of combination therapy with statins and irradiation in androgen-independent prostate cancer cells. PC-3 and LNCaP human prostate cancer cell lines were used in this study. We developed androgen-independent LNCaP cells (LNCaP-LA) by gradually replacing fetal bovine serum (FBS) with charcoal-stripped FBS. Microarray analysis was performed, followed by Ingenuity Pathway Analysis. Cell viability was determined using the MTS assay. Simvastatin alters gene expressions in PC-3 cells. Microarray data showed that the number of differentially expressed genes was the highest in the pathway of "Role of BRCA1 in DNA Damage Response". In the validation, the expression of RAD51, listed in "Role of BRCA1 in DNA Damage Response", decreased significantly by simvastatin in PC-3 cells. Reduction in RAD51 expression following siRNA transfection increased the cytocidal effects of X-ray therapy in PC-3 and LNCaP-LA cells. The combination of simvastatin and irradiation further inhibited cell proliferation compared with monotherapy with either therapy in PC-3 or LNCaP-LA cells. In addition, compared with X-ray monotherapy, the combination of simvastatin and irradiation further enhanced the expression of γH2AX, which is reported to be one of the accurate markers of DNA damage in PC-3 cells. Simvastatin decreased the expression of RAD51 in androgen-independent prostate cancer cells. The combination of irradiation and drugs that reduce RAD51 expression can potentially affect androgen-independent prostate cancer growth.

The Effect of Bitter Melon Extract on Cholesterol, IL-6, and Malondialdehyde Serum Levels

Hypercholesterolemia is a condition by an increase total cholesterol and Low Density Lipoprotein (LDL) cholesterol levels, which can lead the secretion of proinflammatory cytokines Interleukin-6 (IL-6) through the activation of the NF-kB pathway oxidative stress, and increase in Malondialdehyde (MDA) levels. Studies showed that the extract of bitter melon contains flavonoids as antioxidants can reduce cholesterol levels. To find out the effect of bitter melon extract on total cholesterol levels, IL-6, and MDA in hypercholesterolemic rats. Experimental research with Post Test Only Group Design. The research subjects were 25 wistar rats divided into 5 groups. Group K(N) normal rats, K(-) were only given a hypercholesterol diet for 28 days, groups K(+), P1, and P2 were given a hypercholesterol diet for 14 days followed by 14 days of hypercholesterol diet along with simvastatin at 0.09 mg/kgBW, bitter melon extract at 150 mg/kgBW, and combination of bitter melon extract at 75 mg/kgBW and simvastatin at 0.045 mg/kgBW. On the 29th day the rats were examined. The results of the Shapiro-Wilk and Levene tests showed that the data were normally distributed and homogenous. One-Way ANOVA and Tukey test was found that the levels of cholesterol, IL-6, and MDA in the P1, P2, and P3 hypercholesterolemic rat groups underwent significantly (p0.05) compared to the control group. The extract of bitter melon, simvastatin, and the combination of simvastatin and bitter melon extract have effect on reducing cholesterol levels, IL-6, and MDA in hypercholesterolemic rats.

Enhanced therapeutic efficacy of doxorubicin/cyclophosphamide in combination with pitavastatin or simvastatin against breast cancer cells

Fighting breast tumors mandates finding different agents devoid of chemotherapy side effects. Repurposing existing drugs, such as statins, presents a promising avenue for the development of novel cancer therapeutics. Based on the different effects of statin members, this study aims to evaluate the effect of two of the most promising lipophilic statins, Simvastatin and Pitavastatin, and their combination with a conventional chemotherapeutic regimen of doxorubicin and cyclophosphamide on breast cancer cells. MDA-MB-231 and MCF7 cell lines were used to analyze the effects of Pitavastatin and simvastatin in combination with doxorubicin/cyclophosphamide. Cell viability and cell cycle were analyzed and certain apoptosis-related genes such as Bax, Bcl2, and caspase-3, besides cyclin D1 were analyzed using qPCR. The viability of breast cancer cells decreased significantly after treatment with a doxorubicin/cyclophosphamide combination in the presence of Pitavastatin or simvastatin compared with dual doxorubicin/cyclophosphamide with a higher effect in MDA-MB-231 cells than MCF7. In MDA-MB-231, The triple combination of Pitavastatin or simvastatin with doxorubicin/cyclophosphamide resulted in an increase in the expression levels of apoptotic markers than treatment with doxorubicin/cyclophosphamide combination (Bax (p-value = 0.09& 0.02, respectively), Bax/Bcl2 ratio (p-value = 0.0002& <0.0001, respectively)). However, the increase in caspase3 wasn’t significant (p-value = 0.45& 0.09, respectively). Moreover, the expression of cyclin D1 decreased (p-value = 0.0002& <0.0001, respectively) and the cell cycle was arrested in the G1 phase. Combination of Pitavastatin or simvastatin with doxorubicin/ cyclophosphamide may induce apoptosis in breast cancer cells via upregulation of the Bax/Bcl2 pathway, potentially providing a promising new therapeutic strategy for breast cancer.

Simvastatin Induces Autophagy and Inhibits Proliferation in Prostate Cancer Cells.

Statin has recently been studied for its effects on inducing cell death and inhibiting metastasis. Nevertheless, the precise mechanism of its anti-tumor effect is not yet fully understood. We conducted research on statin as a novel treatment for castration-resistant prostate cancer (CRPC). This study focused on autophagy in prostate cancer cells and assessed the effects of simvastatin. After administering simvastatin to PC-3 cells, we conducted a microarray analysis. Simvastatin was administered to prostate cancer cell lines (PC-3, LNCaP-LA; cultured under androgen-depleted conditions, DU145, 22RV1), and the tumor proliferation inhibition was evaluated using the MTS assay and cell count. Autophagy was measured by observing autophagosome staining under a fluorescence microscope and quantifying LC-3 protein using western blot. We also investigated the effects of rapamycin, an autophagy inducer, and chloroquine as an inhibitor. Simvastatin demonstrated a significant concentration-dependent growth inhibition effect on prostate cell lines. Moreover, a significant increase in autophagy was observed in all cell lines following simvastatin administration. When we administered simvastatin with rapamycin at a concentration that did not show a tumor growth inhibitory effect, it significantly enhanced autophagy induction compared to simvastatin alone, and also significantly enhanced the growth inhibition effect on PC-3 cells. Simvastatin induced autophagy and inhibited the proliferation of prostate cancer cell lines. The combination of simvastatin and rapamycin significantly induced autophagy and enhanced the inhibitory effect of simvastatin on proliferation. This mechanism may serve as a novel therapeutic target.

Enhancing anti-cancer potential by delivering synergistic drug combinations via phenylboronic acid modified PLGA nanoparticles through ferroptosis-based therapy

In this study, we investigated the potential of the sorafenib (SOR) and simvastatin (SIM) combination to induce ferroptosis-mediated cancer therapy. To enhance targeted drug delivery, we encapsulated the SOR + SIM combination within 4-carboxy phenylboronic acid (CPBA) modified PLGA nanoparticles (CPBA-PLGA(SOR + SIM)-NPs). The developed CPBA-PLGA(SOR + SIM)-NPs exhibited a spherical shape with a size of 213.1 ± 10.9 nm, a PDI of 0.22 ± 0.03, and a Z-potential of −22.9 ± 3.2 mV. Notably, these nanoparticles displayed faster drug release at acidic pH compared to physiological pH. In cellular experiments, CPBA-PLGA(SOR + SIM)-NPs demonstrated remarkable improvements, leading to a 2.51, 2.69, and 2.61-fold decrease in IC50 compared to SOR alone, and a 7.50, 16.71, and 5.11-fold decrease in IC50 compared to SIM alone in MDA-MB-231, A549, and HeLa cells, respectively. Furthermore, CPBA-PLGA(SOR + SIM)-NPs triggered a reduction in glutathione (GSH) levels, an increase in malondialdehyde (MDA) levels, and mitochondrial membrane depolarization in all three cell lines. Pharmacokinetic evaluation revealed a 2.50- and 2.63-fold increase in AUC0-∞, as well as a 1.53- and 2.46-fold increase in mean residence time (MRT) for SOR and SIM, respectively, compared to the free drug groups. Notably, the CPBA-PLGA(SOR + SIM)-NPs group exhibited significant reduction in tumor volume, approximately 9.17, 2.45, and 1.63-fold lower than the control, SOR + SIM, and PLGA(SOR + SIM)-NPs groups, respectively. Histological examination and biomarker analysis showed no significant differences compared to the control group, suggesting the biocompatibility of the developed particles for in-vivo applications. Altogether, our findings demonstrate that CPBA-PLGA(SOR + SIM)-NPs hold tremendous potential as an efficient drug delivery system for inducing ferroptosis, providing a promising therapeutic option for cancer treatment.

Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome.

Acombination of chemotherapy with immunotherapy has been proposed to have better clinical outcomes in Pancreatic Ductal Adenocarcinoma (PDAC). On the other hand, chemotherapeutics is known to have certain unwanted effects on the tumor microenvironment that may mask the expected beneficial effects of immunotherapy. Here, we have investigated the effect of gemcitabine (GEM), on two immune checkpoint proteins (PD-L1 and PD-L2) expression in cancer associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Findings of in vitro studies conducted by using in-culture activated mouse pancreatic stellate cells (mPSCs) and human PDAC patients derived CAFs demonstrated that GEM significantly induces PD-L1 and PD-L2 expression in these cells. Moreover, GEM induced phosphorylation of STAT1 and production of multiple known PD-L1-inducing secretory proteins including IFN-γ in CAFs. Upregulation of PD-L1 in PSCs/CAFs upon GEM treatment caused T cell inactivation and apoptosis in vitro. Importantly, Statins suppressed GEM-induced PD-L1 expression both in CAFs and PCCs while abrogating the inactivation of T-cells caused by GEM-treated PSCs/CAFs. Finally, in an immunocompetent syngeneic orthotopic mouse pancreatic tumor model, simvastatin and GEM combination therapy significantly reduced intra-tumor PD-L1 expression and noticeably reduced the overall tumor burden and metastasis incidence. Together, the findings of this study have provided experimental evidence that illustrates potential unwanted side effects of GEM that could hamper the effectiveness of this drug as mono and/or combination therapy. At the same time the findings also suggest use of statins along with GEM will help in overcoming these shortcomings and warrant further clinical investigation.

Evaluation of Enhanced Cytotoxicity Effect of Repurposed Drug Simvastatin/Thymoquinone Combination against Breast Cancer Cell Line.

Repurposing of drugs for their anticancer potential is gaining a lot of importance in drug discovery. The present study aims to explore the potential of Simvastatin (SIM), a drug used in the treatment of high cholesterol, and Thymoquinone (Nigella Sativa) (THY) for its anti-cancer activity on breast cancer cell lines. Thymoquinone is reported to have many potential medicinal properties exhibiting antioxidant, antiinflammatory, anti-cancer, activities like inhibition of tissue growth and division. In this analysis, we explored the inhibitory effects of the combination of Simvastatin ad Thymoquinone on two breast cancer cell lines viz MCF-7 and MDA-MB-231 cells. The combined effect of Simvastatin and Thymoquinone on Cell viability, Colony formation, Cell migration, and orientation of more programmed cell death in vitro was studied. Cell cycle arrest in the G2/M phase was concomitant with the combined effect of SIM and THY persuading apoptosis and generating reactive oxygen species (ROS). The cell cycle arrest with combined treatment was observed that only 1.8% and 1.1% cells gated in G2/M phase in MCF-7 & MDA-MB-231 cell. An increased apoptosis was observed when cells were treated in combination which was about 76.20% and 58.15% respectively for MCF-7 and MDA-MB-231 cells. It was concluded that the combined effect of simvastatin and thymoquinone stimulates apoptosis in breast cancer cells.

Exploring Sorafenib and Simvastatin Combination for Ferroptosis-Induced Cancer Treatment: Cytotoxicity Screening, In Vivo Efficacy, and Safety Assessment.

Ferroptosis, a pathway dependent on oxygen and iron catalysts, holds promise as a therapeutic approach for cancer treatment due to its manageable regulation, direct control, and immunogenic properties. The sensitivity of cancer cells to ferroptosis induction varies based on their metabolic, genetic, and signalling pathways, prompting the use of combination therapy. In this study, we conducted a screening of drug combinations, including sorafenib (SOR) with simvastatin (SIM), phenethyl isothiocyanate, and trigonelline, in MDA-MB-231, A549, and HeLa cells to assess their cytotoxicity. The SOR-SIM combination exhibited a synergistic effect in MDA-MB-231, A549, and HeLa cells, with calculated CI values of ~ 0.66, 0.53, and 0.59, respectively. Furthermore, co-treatment with ferrostatin-1 resulted in a concentration-dependent increase in the IC50 values. Additionally, SOR + SIM demonstrated a significant reduction in GSH levels, an increase in MDA levels, and mitochondrial membrane depolarization across all three cell lines, indicating their ferroptosis inducing potential. In-vivo studies showed a significant reduction in tumor volume by 3.53-, 2.55-, and 1.47-fold compared to control, SIM, and SOR, respectively. Toxicity assessments revealed insignificant changes in biomarker levels and no observable deformations in isolated organs, except for erythrocyte shrinkage and membrane scrambling effects caused by the SOR + SIM combination. Overall, our findings highlight the potential of the SOR + SIM combination as an effective strategy for cancer treatment, emphasizing the importance of further research in targeted drug delivery systemsto ensure itssafety.

Effect of Ezetimibe combined with Simvastatin in the treatment of coronary heart disease: a retrospective analysis.

The aim of this study was to explore the effect of Ezetimibe combined with Simvastatin in the treatment of coronary heart disease (CHD). Clinical data of 101 patients with CHD, admitted to our hospital from February 2022 to May 2023, were retrospectively analyzed. Among them, 49 patients received Simvastatin (Simvastatin group), and 52 patients received Simvastatin+Ezetimibe (Simvastatin+Ezetimibe group). Levels of blood lipid indicators, inflammatory factors, cardiac function indicators, and incidences of major adverse cardiovascular events (MACE) between the two groups were compared before and after the treatment. After the treatment, high-density lipoprotein cholesterol (HDL-C), cardiac index (CI), and left ventricular ejection fraction (LVEF) in both groups were higher than those before the treatment, and overall higher in the Simvastatin+Ezetimibe group. Levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), monocyte chemoattractant protein-1 (MCP-1), chemokine ligand 19 (CCL19), high sensitivity C-reactive protein (hs-CRP), cardiac output (CO) in the two groups were lower than before the treatment. These indexes were significantly lower in the Simvastatin+Ezetimibe group (p<0.05) compared to the Simvastatin group. During the treatment, the incidence of MACE in the Simvastatin+Ezetimibe group (3.85%) was significantly lower than that in the Simvastatin group (16.33%) (p<0.05). Compared with Simvastatin alone, a combination of Ezetimibe and Simvastatin can more effectively regulate the level of blood lipids, reduce the inflammatory reaction in the body, improve heart function, and lower the risk of MACE.

Efficacy of Combination of Biodentine and Simvastatin as Pulp Capping Materials in Vital Pulpotomy of Primary Molars: Randomized Clinical Trial

Efficacy of Combination of Biodentine and Simvastatin as Pulp Capping Materials in Vital Pulpotomy of Primary Molars: Randomized Clinical Trial