Showing papers on "Lovastatin published in 2023"

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models

Abstract: Background Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. Methods We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. Results Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. Conclusions These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.

Ethnicity based differences in statin use and hypercholesterolemia control among patients with premature coronary artery disease-results of I-PAD study

Abstract: Statins use is the most important treatment for high LDL cholesterol in patients with premature coronary artery disease (CAD). Previous reports have shown racial and gender differences in statin use in the general population, but this wasn't studied in premature CAD based on different ethnicities.Our study includes 1917 men and women with confirmed diagnosis of premature CAD. Logistic regression model was used to evaluate the high LDL cholesterol control in the groups and the OR with 95% confidence interval (CI) was reported as the effect size. After adjustment for confounders, the odds of controlling LDL in women taking Lovastatin, Rosuvastatin, and Simvastatin were 0.27 (0.03, 0.45) lower in comparison with men. Also, in participant who took 3 types of statins, the odds of controlling LDL were significantly different between Lor and Arab compared with Fars ethnicity. After adjustment to all confounders (full model), the odds of controlling LDL were lower for Gilak in Lovastatin, Rosuvastatin, and Simvastatin by 0.64 (0.47, 0.75); 0.61 (0.43, 0.73); 0.63 (0.46, 0.74) respectively and higher for Arab in Lovastatin, Rosuvastatin, and Simvastatin by 4.63 (18.28, 0.73); 4.67 (17.47, 0.74); 4.55 (17.03, 0.71) respectively compared to Fars.Major differences in different gender and ethnicities may have had led to disparities in statin use and LDL control. Awareness of the statins impact on high LDL cholesterol based on different ethnicities can help health decision-makers to close the observed gaps in statin use and control LDL to prevent CAD problems.

The Questionable Quality Profile of Food Supplements: The Case of Red Yeast Rice Marketed Products

Abstract: Food supplements (FS) containing red yeast rice (RYR) are largely employed to reduce lipid levels in the blood. The main ingredient responsible for biological activity is monacolin K (MoK), a natural compound with the same chemical structure as lovastatin. Concentrated sources of substances with a nutritional or physiological effect are marketed in “dose” form as food supplements (FS). The quality profile of the “dosage form” of FS is not defined in Europe, whereas some quality criteria are provided in the United States. Here, we evaluate the quality profile of FS containing RYR marketed in Italy as tablets or capsules running two tests reported in The European Pharmacopoeia 11 Ed. and very close to those reported in the USP. The results highlighted variations in dosage form uniformity (mass and MoK content) compliant with The European Pharmacopoeia 11 Ed. specifications, whereas the time needed for disintegrating tablets was longer for 44% of the tested samples. The bioaccessibility of MoK was also investigated to obtain valuable data on the biological behaviour of the tested FS. In addition, a method for citrinin (CIT) determination was optimized and applied to real samples. None of the analyzed samples demonstrated CIT contamination (LOQ set at 6.25 ng/mL). Considering the widespread use of FS, our data suggest that greater attention should be paid by fabricants and regulatory authorities to ensure the quality profile and the safe consumption of marketed products.

Supplementary Tables 1-3, Supplementary Figures 1-7 from Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

Abstract: <p>Supplementary Tables 1-3, Supplementary Figures 1-7. Supplementary Table 1: Oligonucleotide primers used for qRT-PCR analysis. Supplementary Table 2: GSEA enrichment of KEGG functional pathways in lovastatin-regulated genes. Supplementary Table 3: Lovastatin affects expression of genes in glycolysis/gluconeogenesis pathway. Supplementary Figure 1: Daily administration of lovastatin prevents tumor growth in mogp-TAg transgenic mice. Supplementary Figure 2: Body weight and serum levels of cholesterol and triglyceride in mogp-TAg, SKOV3-IP, and OVCAR5 mouse tumor models. Supplementary Figure 3: Atorvastatin treatment delays growth of ovarian tumor xenografts. Supplementary Figure 4: Statin treatment increases transcript levels of LC3A and LC3B. Supplementary Figure 5: Scheme of the mevalonate pathway. Supplementary Figure 6: Applying GGPP or FPP as a single agent does not affect ovarian cancer cell proliferation. Supplementary Figure 7: Real-time qRT-PCR confirms knockdown efficiency of each siRNA.</p>

Research Progress on Gene Synthesis and Anticancer and Lipid-lowering Mechanism of Monacolin K.

Abstract: Monacolin K (MK), also known as lovastatin (LOV), is a secondary metabolite synthesized by Monascus in the later stage of fermentation and is the main component of functional red yeast rice (RYR). The structure of MK is similar to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and it can competitively bind to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), thus reducing the level of blood lipids. MK can affect the expression of MAPK, PI3K/AKT, and NF-κB pathway, prepare conjugates with other compounds, and enhance the sensitivity of cancer cells to chemotherapeutic drugs so as to induce apoptosis of acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, and liver cancer. Combined with the synthetic route of MK, this paper summarizes the latest lipid-lowering and anticancer mechanism of MK, and provides a reference for the application of MK in medicine.

Supplementary Tables 1 - 2 from A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial of Lovastatin for Various Endpoints of Melanoma Pathobiology

Abstract: <p>PDF file - 64KB, Supplementary Table S1. Descriptive statistics for concordance evaluation of positive control slides. Supplementary Table S2. Evaluation of laboratory data.</p>

Supplementary Tables 1 - 2 from A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial of Lovastatin for Various Endpoints of Melanoma Pathobiology

Abstract: <p>PDF file - 64KB, Supplementary Table S1. Descriptive statistics for concordance evaluation of positive control slides. Supplementary Table S2. Evaluation of laboratory data.</p>

Supplementary Table S1 from Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Abstract: <p>PDF file - 84 KB, Differentially expressed cells in genes upon exposure to 20 muM lovastatin in resistant MM cell lines (LP1).</p>

Supplementary Figure 3 from The Role of Specific ATP-Binding Cassette Transporters in the Acquired Resistance to Pyrrolobenzodiazepine Dimer–Containing Antibody–Drug Conjugates

Abstract: <p>Supplementary Figure 3. Reversing the acquired PBD or PBD-based ADC resistance with ABC drug transporter inhibitors. A. Continuous exposure in vitro growth inhibition of Karpas-299 wt, ADC and PBD resistant cell lines with ADCT-301 and 10 nM Lovastatin. B. Continuous exposure in vitro growth inhibition of NCI-N87 wt, ADC and PBD resistant cell lines with ADCT-502 and 5 µM Lovastatin. Each data point represents the average of at least 3 biological repeats with +/- SD error bars.</p>

Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial.

Abstract: Importance Disseminated superficial actinic porokeratosis (DSAP) is an inherited or sporadic disorder of keratinization associated with germline variations. There is no effective standard of care therapy for DSAP, but treatment with topical lovastatin combined with cholesterol cream has shown promise. Objectives To evaluate and compare the safety and efficacy of topical lovastatin 2% plus cholesterol 2% cream (lovastatin-cholesterol) and topical lovastatin 2% cream (lovastatin) alone in adults diagnosed with DSAP. Design, Setting, and Participants This patient- and assessor-blinded, randomized clinical trial was conducted at the Medical University of South Carolina between August 3, 2020, and April 28, 2021. Nonpregnant adults with a previous clinical or histological diagnosis of DSAP were eligible. Data were blindly analyzed after study completion. Interventions Participants were randomized to once- or twice-daily application of either lovastatin-cholesterol cream (n = 17) or lovastatin cream (n = 14) to symptomatic regions for 12 weeks. Main Outcomes and Measures The primary efficacy measure was the effect of the treatment on DSAP at the end of treatment (12 weeks) as measured by the DSAP General Assessment Severity Index (DSAP-GASI; scored from 0-4, with 0 indicating clear and 4 indicating severe). Treatment efficacy was based on investigator-standardized photographs provided by the participants because of the need for evaluation via telehealth during the COVID-19 pandemic. Secondary efficacy measures included patient-reported outcomes, application frequency, and adverse events (AEs). Results Of the 87 participants screened, 32 were enrolled. One participant randomized to receive lovastatin-cholesterol did not receive the intervention, leaving 17 participants (mean [range] age, 59.2 [40-83] years; 13 females [76.5%]; all White) allocated to receive lovastatin-cholesterol treatment and 14 participants (13 female [92.9%]; mean (range) age, 53.7 [33-71] years; all White) to receive lovastatin treatment. Twelve participants in each treatment group qualified for the analysis. Disease severity decreased from week 1 to week 12 by 50.0% (from 3.08 [95% CI, 2.57-3.60] to 1.54 (95% CI, 1.04-2.05] points on the DSAP-GASI; P < .001) in the lovastatin-cholesterol group and 51.4% (from 2.92 [95% CI, 2.40-3.43] to 1.50 [95% CI, 0.99-2.01] points; P < .001) in the lovastatin group. There was no significant difference between the treatment groups according to application frequency at the end of 12 weeks. Adverse events reported included myalgia (n = 2), elevation in the creatine kinase level (n = 1), application discomfort (n = 4), and rash (n = 1). No serious AEs occurred, and all participants with an AE were able to complete the study. Conclusions and Relevance This randomized clinical trial found improvements in DSAP severity in both treatment groups, without serious AEs, indicating a limited benefit with the addition of cholesterol. These results suggest that lovastatin cream may be a new primary treatment option for patients diagnosed with DSAP. Trial Registration ClinicalTrials.gov Identifier: NCT04359823.

Development and Validation of RP- HPLC Method for Simultaneous Determination of Niacin (Extended Release) and Lovastatin in Oral Solid Dosage Form

Abstract: The present study aimed to develop a novel RP-HPLC Method for the estimation of Niacin and Lovastatin in Bulk and oral solid dosage form. For the simultaneous estimation of lovastatin and niacin in a combined dosage form, a straightforward, accurate, and speedy HPLC method has been created and validated. Chromatographic separation of the two drugs was performed on a Purospher BDS C8 column (150 mm× 4.6 mm id, 5µm particle size). The mobile phase used was a mixture of 0.1% v/v triethylamine (pH 5.0), containing 20 mM of Ammonium acetate buffer: methanol (30:70% v/v).Detection was performed at 237nm and sharp peaks were obtained for niacin and Lovastatin at retention times of 3.2±0.01 min and.6.4±0.01 min respectively. The calibration curve was linear in the concentration range 100-700µg/ml for niacin 3-18µg/ml for Lovastatin; the correlation coefficients were 0.9991 and 0.9992, respectively. According to the International Conference on Harmonization (ICH) Q2 (R1) guidelines, the optimised method performed well in terms of specificity, linearity, detection and quantitation limits, precision, and accuracy. It has been shown that this assay can be used to regularly quantify lovastatin and niacin in tablet dosage form. High percentage recovery of drug shows the method is free from inference of excipients present in the formulation. The proposed method was found suitable for simultaneous analysis of NI and LT can be used for routine quality control of their bulk drug mixture and their combined dosage form.

Data from A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial of Lovastatin for Various Endpoints of Melanoma Pathobiology

Abstract: <div>Abstract<p>On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. <i>Cancer Prev Res; 7(5); 496–504. ©2014 AACR</i>.</p></div>

Rhabdomyolysis and statins: A pharmacovigilance comparative study between statins

Abstract: Rhabdomyolysis is a serious adverse drug reaction of statins. There are few studies comparing the risk of rhabdomyolysis between the different statins. Using the WHO pharmacovigilance database, VigiBase®, we compared the risk of rhabdomyolysis reporting of seven statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, with cerivastatin excluded). All reports of rhabdomyolysis in VigiBase® in adults with statins until 31 December 2022 were included. Results are expressed as reporting odds ratio (ROR, 95% CI). Among 10 657 reports with rhabdomyolysis with statins, simvastatin was the highest risk statin in comparison with others: ROR = 2.20 (2.11–2.29). The risk was higher in men, older than 74 years and in cases of drug interactions.

Data from Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Abstract: <div>Abstract<p>Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (<i>P</i> = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007;6(6):1886–97]</p></div>

Exploitation of Sugarcane Bagasse and Environmentally Sustainable Production, Purification, Characterization, and Application of Lovastatin by Aspergillus terreus AUMC 15760 under Solid-State Conditions

Abstract: Using the internal transcribed spacer (ITS) region for identification, three strains of Aspergillus terreus were identified and designated AUMC 15760, AUMC 15762, and AUMC 15763 for the Assiut University Mycological Centre culture collection. The ability of the three strains to manufacture lovastatin in solid-state fermentation (SSF) using wheat bran was assessed using gas chromatography-mass spectroscopy (GC-MS). The most potent strain was strain AUMC 15760, which was chosen to ferment nine types of lignocellulosic waste (barley bran, bean hay, date palm leaves, flax seeds, orange peels, rice straw, soy bean, sugarcane bagasse, and wheat bran), with sugarcane bagasse turning out to be the best substrate. After 10 days at pH 6.0 at 25 °C using sodium nitrate as the nitrogen source and a moisture content of 70%, the lovastatin output reached its maximum quantity (18.2 mg/g substrate). The medication was produced in lactone form as a white powder in its purest form using column chromatography. In-depth spectroscopy examination, including 1H, 13C-NMR, HR-ESI-MS, optical density, and LC-MS/MS analysis, as well as a comparison of the physical and spectroscopic data with published data, were used to identify the medication. At an IC50 of 69.536 ± 5.73 µM, the purified lovastatin displayed DPPH activity. Staphylococcus aureus and Staphylococcus epidermidis had MICs of 1.25 mg/mL, whereas Candida albicans and Candida glabrata had MICs of 2.5 mg/mL and 5.0 mg/mL, respectively, against pure lovastatin. As a component of sustainable development, this study offers a green (environmentally friendly) method for using sugarcane bagasse waste to produce valuable chemicals and value-added commodities.

Data from Statin-Induced Breast Cancer Cell Death: Role of Inducible Nitric Oxide and Arginase-Dependent Pathways

Abstract: <div>Abstract<p>Statins are widely used cholesterol-lowering drugs that selectively inhibit the enzyme 3-hydroxy-3-methylglutaryl CoA reductase, leading to decreased cholesterol biosynthesis. Emerging data indicate that statins stimulate apoptotic cell death in several types of proliferating tumor cells, including breast cancer cells, which is independent of its cholesterol-lowering property. The objective here was to elucidate the molecular mechanism(s) by which statins induce breast cancer cell death. Fluvastatin and simvastatin (5–10 μmol/L) treatment enhanced the caspase-3–like activity and DNA fragmentation in MCF-7 cells, and significantly inhibited the proliferation of MCF-7 cells but not MCF-10 cells (noncancerous epithelial cells). Statin-induced cytotoxic effects were reversed by mevalonate, an immediate metabolic product of the acetyl CoA/3-hydroxy-3-methylglutaryl CoA reductase reaction. Both simvastatin and fluvastatin enhanced nitric oxide (^·NO) levels which were inhibited by mevalonate. Statin-induced ^·NO and tumor cell cytotoxicity were inhibited by 1400W, a more specific inhibitor of inducible nitric oxide synthase (iNOS or NOS II). Both fluvastatin and simvastatin increased iNOS mRNA and protein expression. Stimulation of iNOS by statins via inhibition of geranylgeranylation by GGTI-298, but not via inhibition of farnesylation by FTI-277, enhanced the proapoptotic effects of statins in MCF-7 cells. Statin-mediated antiproliferative and proapoptotic effects were exacerbated by sepiapterin, a precursor of tetrahydrobiopterin, an essential cofactor of ^·NO biosynthesis by NOS. We conclude that iNOS-mediated ^·NO is responsible in part for the proapoptotic, tumoricidal, and antiproliferative effects of statins in MCF-7 cells. [Cancer Res 2007;67(15):7386–94]</p></div>

Protective Effects of Lovastatin in a Population‐Based ALS Study and Mouse Model

Abstract: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications.

Lovastatin inhibits erythroleukemia progression through KLF2-mediated suppression of MAPK/ERK signaling

Abstract: Lovastatin, an HMG-CoA inhibitor and an effective cholesterol lowering drug, exhibits anti-neoplastic activity towards several types of cancer, although the underlying mechanism is still not fully understood. Herein, we investigated mechanism of growth inhibition of leukemic cells by lovastatin.RNAseq analysis was used to explore the effect of lovastatin on gene expression in leukemic cells. An animal model of leukemia was used to test the effect of this statin in vivo. FAM83A and DDIT4 expression was knocked-downed in leukemia cells via lentivirus-shRNA. Western blotting, RT-qPCR, cell cycle analysis and apoptosis assays were used to determine the effect of lovastatin-induced growth suppression in leukemic cells in vitro.Lovastatin treatment strongly inhibited cancer progression in a mouse model of erythroleukemia induced by Friend virus. In tissue culture, lovastatin inhibited cell proliferation through induction of G1 phase cell cycle arrest and apoptosis. Interestingly, lovastatin induced most known genes associated with cholesterol biosynthesis in leukemic cells. Moreover, it suppressed ERK1/2 phosphorylation by downregulating FAM83A and DDIT4, two mediators of MAP-Kinase signaling. RNAseq analysis of lovastatin treated leukemic cells revealed a strong induction of the tumor suppressor gene KLF2. Accordingly, lentivirus-mediated knockdown of KLF2 antagonized leukemia cell suppression induced by lovastatin, associated with higher ERK1/2 phosphorylation compared to control. We further show that KLF2 induction by lovastatin is responsible for lower expression of the FAM83A and DDIT4 oncogenes, involved in the activation of ERK1/2. KLF2 activation by lovastatin also activated a subset of cholesterol biosynthesis genes that may further contribute to leukemia suppression.These results implicate KLF2-mediated FAM83A/DDIT4/MAPK suppression and activation of cholesterol biosynthesis as the mechanism of leukemia cell growth inhibition by lovastatin.

Lovastatin for lowering lipids

Abstract: Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To evaluate the benefits and harms of different doses of lovastatin on lipid parameters and withdrawals due to adverse effects (WDAEs) in people of any age compared to placebo.

Data from Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

Abstract: <div>Abstract<p><b>Purpose:</b> Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with <i>TP53</i> mutations. Because <i>TP53</i> mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer.</p><p><b>Experimental Design:</b> Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated.</p><p><b>Results:</b> Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells.</p><p><b>Conclusions:</b> The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. <i>Clin Cancer Res; 21(20); 4652–62. ©2015 AACR</i>.</p></div>

Supplementary Tables 1-3, Supplementary Figures 1-7 from Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

Abstract: <p>Supplementary Tables 1-3, Supplementary Figures 1-7. Supplementary Table 1: Oligonucleotide primers used for qRT-PCR analysis. Supplementary Table 2: GSEA enrichment of KEGG functional pathways in lovastatin-regulated genes. Supplementary Table 3: Lovastatin affects expression of genes in glycolysis/gluconeogenesis pathway. Supplementary Figure 1: Daily administration of lovastatin prevents tumor growth in mogp-TAg transgenic mice. Supplementary Figure 2: Body weight and serum levels of cholesterol and triglyceride in mogp-TAg, SKOV3-IP, and OVCAR5 mouse tumor models. Supplementary Figure 3: Atorvastatin treatment delays growth of ovarian tumor xenografts. Supplementary Figure 4: Statin treatment increases transcript levels of LC3A and LC3B. Supplementary Figure 5: Scheme of the mevalonate pathway. Supplementary Figure 6: Applying GGPP or FPP as a single agent does not affect ovarian cancer cell proliferation. Supplementary Figure 7: Real-time qRT-PCR confirms knockdown efficiency of each siRNA.</p>

Enhancing Lovastatin Biosynthesis in Oyster Mushrooms (Pleurotus ostreatus) using Phytohormones

Abstract: The biosynthesis of lovastatin, the anti-cholesterol compound, in oyster mushrooms (Pleurotus ostreatus), has the potential to be enhanced by utilizing phytohormones, which activate the expression of certain genes. This research aimed to determine the best type and concentration of phytohormone among auxin, gibberellin, and cytokinin, as well as the best mycelial colonization percentage in F2 medium to realize the greatest increase in lovastatin biosynthesis in oyster mushrooms. Lovastatin was extracted from the fruiting bodies and mycelia and analyzed by spectrophotometry. The analysis of CYP450 linked to lovastatin biosynthesis was conducted by quantitative polymerase chain reaction (qPCR) using samples containing the highest concentration of lovastatin. The results showed that adding phytohormones increased the lovastatin concentration in the fruiting bodies and mycelia of P. ostreatus. The highest lovastatin content was observed in the 10 ppm gibberellin treatment by applying 75% mycelial colonization in the F2 medium. Furthermore, this gibberellin treatment also demonstrated increased expression of the CYP450 gene in the fruiting bodies and mycelia. In conclusion, phytohormone treatments with the right timing and appropriate concentration increased lovastatin biosynthesis in P. ostreatus as well as related gene expression.

Association between Statins Types with Incidence of Liver Cancer: An Updated Meta-analysis.

Abstract: BACKGROUND Previous studies have found a potential role for statins in liver cancer prevention. OBJECTIVE This study aimed to explore the effect of different types of statins on the incidence of liver cancer. METHOD Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer. RESULTS Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p<0.001) and hydrophilic statins (OR=0.56, p<0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p<0.001; Western countries: OR=0.59, p<0.001) and hydrophilic (Eastern countries: OR=0.51, p<0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p<0.001), simvastatin (OR=0.59, p<0.001), lovastatin (OR=0.51, p<0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin Conclusion: Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.

Data from Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Abstract: <div>Abstract<p>Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (<i>P</i> = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007;6(6):1886–97]</p></div>

Bioinformatic Analysis of Key Regulatory Genes in Adult Asthma and Prediction of Potential Drug Candidates

Abstract: Asthma is a common chronic disease that is characterized by respiratory symptoms including cough, wheeze, shortness of breath, and chest tightness. The underlying mechanisms of this disease are not fully elucidated, so more research is needed to identify better therapeutic compounds and biomarkers to improve disease outcomes. In this present study, we used bioinformatics to analyze the gene expression of adult asthma in publicly available microarray datasets to identify putative therapeutic molecules for this disease. We first compared gene expression in healthy volunteers and adult asthma patients to obtain differentially expressed genes (DEGs) for further analysis. A final gene expression signature of 49 genes, including 34 upregulated and 15 downregulated genes, was obtained. Protein–protein interaction and hub analyses showed that 10 genes, including POSTN, CPA3, CCL26, SERPINB2, CLCA1, TPSAB1, TPSB2, MUC5B, BPIFA1, and CST1, may be hub genes. Then, the L1000CDS2 search engine was used for drug repurposing studies. The top approved drug candidate predicted to reverse the asthma gene signature was lovastatin. Clustergram results showed that lovastatin may perturb MUC5B expression. Moreover, molecular docking, molecular dynamics simulation, and computational alanine scanning results supported the notion that lovastatin may interact with MUC5B via key residues such as Thr80, Thr91, Leu93, and Gln105. In summary, by analyzing gene expression signatures, hub genes, and therapeutic perturbation, we show that lovastatin is an approved drug candidate that may have potential for treating adult asthma.