Review

Authors: Arrigo F G Cicero, Federica Fogacci, Maciej Banach...

The extract of red yeast rice (RYR) is the most effective cholesterol-lowering nutraceutical on the market. In particular, its effectiveness is directly related to the amount of monacolin K within the extract (up to 10 mg/day). Consuming monacolin K on a daily basis reduces low-density lipoprotein (LDL) cholesterol plasma levels between 15% and 25% within 6 to 8 weeks. Certainly, the decrease in LDL-cholesterol is accompanied by a similar reduction in total cholesterol, non-high-density lipoprotein cholesterol, plasma apolipoprotein B, matrix metalloproteinases 2 and 9, and high-sensitivity C-reactive protein. Furthermore, the RYR lipid-lowering effect is associated with significant improvements in pulse wave velocity and endothelial function, which are validated and reliable biomarker tools able to detect vascular aging. Although it has a mechanism of action similar to statins, a daily consumption of between 3 and 10 mg monacolin K has only minimal associated risks, and mild myalgias are seen only in the frailest patients (those who also cannot tolerate minimal dosages of statin). The monacolin K found in RYR is a safe and effective supplement for managing mild to moderate hypercholesterolemia in people with no additional cardiovascular risk factors.

Topics: Animals; Biological Products; Biomarkers; Cholesterol; Dietary Supplements; Down-Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lovastatin; Treatment Outcome

PubMed: 31687098
DOI: 10.14797/mdcj-15-3-192

Review

Authors: Stephanie M Kyle, Neeti Vashi, Monica J Justice...

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of in the central nervous system. However, the variety of phenotypes identified in mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

Topics: Animals; Brain; Disease Models, Animal; Disease Progression; Drug Repositioning; Female; History, 20th Century; Humans; Lipid Metabolism; Lovastatin; Methyl-CpG-Binding Protein 2; Mice; Mutation; Quality of Life; Rett Syndrome

PubMed: 29445033
DOI: 10.1098/rsob.170216

Randomized Controlled Trial

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.

Authors: Gabriella Santa Lucia, Alan Snyder, Almeera Lateef...

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.

Topics: Adult; Humans; Female; Middle Aged; Lovastatin; Porokeratosis; Pandemics; COVID-19; Treatment Outcome; Emollients; Cholesterol

PubMed: 36947042
DOI: 10.1001/jamadermatol.2023.0205

Authors: Vikash Kansal, Andre J Burnham, Brendan L C Kinney...

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.

Topics: Animals; Mice; Squamous Cell Carcinoma of Head and Neck; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune Checkpoint Inhibitors; Head and Neck Neoplasms; Lovastatin; Simvastatin

PubMed: 36650022
DOI: 10.1136/jitc-2022-005940

Authors: Lei Li, Hongbin Wang, Shiyuan Zhang...

BACKGROUND

In recent years, the widespread use of lipid-lowering drugs, especially statins, has attracted people's attention. Statin use may be potentially associated with a reduced risk of breast cancer.

OBJECTIVE

To explore the relationship between statin use and cancer risk. And further explore the potential role of statins in the adjuvant treatment of breast cancer.

METHODS

Data for the Mendelian randomization portion of the study were obtained from genome-wide association studies of common cancers in the UK Biobank and FinnGen studies and from the Global Lipid Genetics Consortium's low density lipoprotein (LDL). In addition, the impacts of statins and chemotherapy drugs on breast cancer were examined using both in vitro and in vivo models, with particular attention to the expression levels of the immune checkpoint protein PD-L1 and its potential to suppress tumor growth.

RESULTS

Data from about 3.8 million cancer patients and ~1.3 million LDL-measuring individuals were analyzed. Genetically proxied HMGCR inhibition (statins) was associated with breast cancer risk reduction (P=0.0005). In vitro experiments showed that lovastatin significantly inhibited paclitaxel-induced PD-L1 expression and assisted paclitaxel in suppressing tumor cell growth. Furthermore, the combination therapy involving lovastatin and paclitaxel amplified CD8+ T-cell infiltration, bolstering their tumor-killing capacity and enhancing in vivo efficacy.

CONCLUSION

The utilization of statins is correlated with improved prognoses for breast cancer patients and may play a role in facilitating the transition from cold to hot tumors. Combination therapy with lovastatin and paclitaxel enhances CD8+ T-cell activity and leads to better prognostic characteristics.

Topics: Breast Neoplasms; B7-H1 Antigen; Female; Paclitaxel; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Prognosis; CD8-Positive T-Lymphocytes; Mice; Animals; Lovastatin; Genome-Wide Association Study

PubMed: 39143707
DOI: 10.1097/JS9.0000000000001582

Review

Authors: Anna Sadowska, Patryk Osiński, Alicja Roztocka...

Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as spp., spp., , and have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects.

Topics: Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacy; Fungi; Lovastatin

PubMed: 38203637
DOI: 10.3390/ijms25010466

Authors: Kirk L Hamilton

Topics: Animals; Apoptosis; Cyclosporine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Tubules, Collecting; Lovastatin; Tight Junctions

PubMed: 23761675
DOI: 10.1152/ajprenal.00321.2013

Review

Authors: Tomasz Boruta, Marcin Bizukojc

Aspergillus terreus is a textbook example of an industrially relevant filamentous fungus. It is used for the biotechnological production of two valuable metabolites, namely itaconic acid and lovastatin. Itaconic acid serves as a precursor in polymer industry, whereas lovastatin found its place in the pharmaceutical market as a cholesterol-lowering statin drug and a precursor for semisynthetic statins. Interestingly, their biosynthetic gene clusters were shown to reside in the common genetic neighborhood. Despite the genomic proximity of the underlying biosynthetic genes, the production of lovastatin and itaconic acid was shown to be favored by different factors, especially with respect to pH values of the broth. While there are several reviews on various aspects of lovastatin and itaconic acid production, the survey on growth conditions, biochemistry and morphology related to the formation of these two metabolites has never been presented in the comparative manner. The aim of the current review is to outline the correlations and contrasts with respect to process-related and biochemical discoveries regarding itaconic acid and lovastatin production by A. terreus.

Topics: Ammonium Compounds; Aspergillus; Fermentation; Glucose; Lactose; Lovastatin; Metabolic Networks and Pathways; Succinates

PubMed: 28102516
DOI: 10.1007/s11274-017-2206-9

Authors: Yi Rao, Zachary Samuels, Lukas M Carter...

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

Topics: Humans; Animals; Mice; Stomach Neoplasms; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmaceutical Preparations; Receptor, ErbB-2; Trastuzumab; Lovastatin; Cell Line, Tumor

PubMed: 36972439
DOI: 10.1073/pnas.2220413120

Review

Authors: Efosa Amadasu, Richard Kang, Ahsan Usmani...

Although brain tumors occur less frequently than other forms of cancer, they have one of the bleakest prognoses with low survival rates. The conventional treatment for brain tumors includes surgery, radiotherapy, and chemotherapy. However, resistance to treatment remains a problem with recurrence shortly following. The resistance to treatment may be caused by cancer stem cells (CSCs), a subset of brain tumor cells with the affinity for self-renewal and differentiation into multiple cell lineages. An emerging approach to targeting CSCs in brain tumors is through repurposing the lipid-lowering medication, lovastatin. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that impacts the mevalonate pathway. The inhibition of intermediates in the mevalonate pathway affects signaling cascades and oncogenes associated with brain tumor stem cells (BTSC). In this review, we show the possible mechanisms where lovastatin can target BTSC for different varieties of malignant brain tumors.

Topics: Brain; Brain Neoplasms; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mevalonic Acid

PubMed: 35670207
DOI: 10.1177/09636897221102903