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Nutrients Oct 2023Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in males worldwide. Early-stage PC patients can...
Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in males worldwide. Early-stage PC patients can benefit from surgical, radiation, and hormonal therapies; however, once the tumor transitions to an androgen-refractory state, the efficacy of treatments diminishes considerably. Recently, the exploration of natural products, particularly dietary phytochemicals, has intensified in response to addressing this prevailing medical challenge. In this study, we uncovered a synergistic effect from combinatorial treatment with lovastatin (an active component in red yeast rice) and (AC, a folk mushroom) extract against PC3 human androgen-refractory PC cells. This combinatorial modality resulted in cell cycle arrest at the G0/G1 phase and induced apoptosis, accompanied by a marked reduction in molecules responsible for cellular proliferation (p-Rb/Rb, Cyclin A, Cyclin D1, and CDK1), aggressiveness (AXL, p-AKT, and survivin), and stemness (SIRT1, Notch1, and c-Myc). In contrast, treatment with either AC or lovastatin alone only exerted limited impacts on the cell cycle, apoptosis, and the aforementioned signaling molecules. Notably, significant reductions in canonical PC stemness markers (CD44 and CD133) were observed in lovastatin/AC-treated PC3 cells. Furthermore, lovastatin and AC have been individually examined for their anti-PC properties. Our findings elucidate a pioneering discovery in the synergistic combinatorial efficacy of AC and clinically viable concentrations of lovastatin on PC3 PC cells, offering novel insights into improving the therapeutic effects of dietary natural products for future strategic design of therapeutics against androgen-refractory prostate cancer.
Topics: Male; Humans; Androgens; PC-3 Cells; Lovastatin; Cell Proliferation; Apoptosis; Prostatic Neoplasms; Biological Products; Cell Line, Tumor
PubMed: 37960146
DOI: 10.3390/nu15214493 -
International Journal of Nanomedicine 2020The aim of the study was to optimize the processing factors of precipitation-ultrasonication technique to prepare nano-sized particles of Lovastatin (LA) for enhancing...
INTRODUCTION
The aim of the study was to optimize the processing factors of precipitation-ultrasonication technique to prepare nano-sized particles of Lovastatin (LA) for enhancing its solubility, dissolution rate and in vivo bioavailability.
METHODS
LA nanoparticles (LANs) were prepared using precipitation-ultrasonication technique under different processing factors. LANs were characterized in terms of particle size, zeta potential and in vitro release. Stability studies at 4°C, 25°C and 40°C were conducted for optimum formulation. In addition, the in vivo bioavailability of the optimum formula was studied in comparison to a marketed product in white master rats.
RESULTS
The optimized LAN formula (LAN15) had particle size (190±15), polydispersity index (0.626±0.11) and a zeta potential (-25±1.9 mV). The dissolution study of the nanosuspensions showed significant enhancement compared with pure drug. After 50 min, only 20.12±1.85% of LA was dissolved while 99.1±1.09% of LA was released from LAN15. Stability studies verified that nanosuspensions at 4°C and 25°C showed higher stability with no particle growth compared to the samples studied at 40°C. In vivo studies conducted in rats verified that there was 1.45-fold enhancement of C of LAN15 as compared to marketed tablets.
CONCLUSION
Nanoparticle prepared by ultrasonication-assisted precipitation method is a promising formula for enhancing the solubility and hence the bioavailability of Lovastatin.
Topics: Administration, Oral; Animals; Biological Availability; Calorimetry, Differential Scanning; Lovastatin; Male; Nanoparticles; Particle Size; Rats, Wistar; Solubility; Spectroscopy, Fourier Transform Infrared; Static Electricity; Suspensions
PubMed: 32606674
DOI: 10.2147/IJN.S241120 -
Nature Communications Feb 2021Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by...
Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB-LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB-LovC complex at 3.60 Å and the core LovB at 2.91 Å resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.
Topics: Biocatalysis; Lovastatin; Models, Molecular; Naphthalenes; Oxidoreductases Acting on CH-CH Group Donors; Polyketide Synthases; Protein Domains; Substrate Specificity
PubMed: 33558520
DOI: 10.1038/s41467-021-21174-8 -
Biomedica : Revista Del Instituto... Dec 2019Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases.
INTRODUCTION
Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases.
OBJECTIVE
To determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population.
MATERIALS AND METHODS
This is a cross-sectional descriptive study. From a drug dispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified between January and March, 2017. Demographic, pharmacological and co-medication variables were included.
RESULTS
In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n=96,910; 93.5%), and atorvastatin (n=80,812; 78.0%) and lovastatin (n=12,621; 12.2%) were the most frequent. The mean atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n=100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%).
CONCLUSIONS
Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.
Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Atorvastatin; Cities; Colombia; Cross-Sectional Studies; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lovastatin; Male; Middle Aged; Sex Distribution; Young Adult
PubMed: 31860186
DOI: 10.7705/biomedica.4801 -
Journal of Nuclear Medicine : Official... Oct 2023The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC)...
The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the Zr-labeled or Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.
Topics: Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Stomach Neoplasms; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Trastuzumab; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Breast Neoplasms; Immunoconjugates; Positron-Emission Tomography; Lovastatin
PubMed: 37385676
DOI: 10.2967/jnumed.122.265172 -
Medicina (Kaunas, Lithuania) Oct 2023: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal...
Pitavastatin and Lovastatin Exhibit Calcium Channel Blocking Activity Which Potentiate Vasorelaxant Effects of Amlodipine: A New Futuristic Dimension in Statin's Pleiotropy.
: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. : Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit's aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. : The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC (7.44 × 10 ± 0.16 M) in intact and (4.55 × 10 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC values for the statins was seen when we added amlodipine in EC (Log Ca M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10 M) produced a right shift in relatively lower EC (-2.5 ± 0.10) Log Ca M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine ( < 0.05). : KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.
Topics: Animals; Rabbits; Vasodilator Agents; Amlodipine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Calcium Channel Blockers; Calcium Channels; Verapamil; Norepinephrine
PubMed: 37893523
DOI: 10.3390/medicina59101805 -
Journal For Immunotherapy of Cancer Jan 2023Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients...
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 -
Molecules (Basel, Switzerland) Apr 2016We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine.
BACKGROUND
We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine.
METHODS
An UPLC-MS/MS method was developed and validated for the pharmacokinetics tudy of lovastatin to investigate the in vivo drug-drug interactions between lovastatin and berberine. SD male rats were random divided into lovastatin group and berberine induced prior to lovastatin group for the in vivo pharmacokinetic studies. Meanwhile HepG2 cells were induced by berberine for three days to study the metabolism of lovastatin.
RESULTS
The AUC (p < 0.01) and Cmax (p < 0.01) could be significantly decreased in the berberine-induced group in vivo, and the metabolic activity of HepG2 cell ccould be increased by berberine induction in vitro. The metabolism parameters of lovastatin such as CL, Vmax and Km were increased after the induction of berberine. From the pharmacokinetic study of lovastatin induced with berberine, we obtained pharmacokinetic parameters which are compliance with the metabolic parameters of lovastatin in HepG2 cells with berberine induction in vitro.
CONCLUSIONS
From the in vivo pharmacokinetics study and the HepG2 cell metabolism study in vitro, berberine could be an inducer for the metabolism of lovastatin according to our previous research on berberine induction effects on HepG2 cells, which may be relevant to the fact that berberine possesses induction effects through the CYP 450 3A4 enzyme.
Topics: Animals; Berberine; Cytochrome P-450 CYP3A; Drug Interactions; Hep G2 Cells; Humans; Lovastatin; Rats
PubMed: 27070564
DOI: 10.3390/molecules21040464 -
BMC Cancer Apr 2021Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types...
BACKGROUND
Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain.
METHODS
We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using a neutral cellular substrate, Saccharomyces cerevisiae. Cell density (OD) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software.
RESULTS
Four of the ten chemotherapy drugs - tamoxifen, doxorubicin, methotrexate and rapamycin - exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Two drug pairs, lovastatin combined with tamoxifen or cisplatin, were also assayed in human cell lines as proof of principle.
CONCLUSIONS
The synergistic interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin - because they suggest the possibility of clinical utility - merit further exploration and validation in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to any chemotherapeutic regimen. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.
Topics: Anticholesteremic Agents; Drug Antagonism; Drug Synergism; Humans; Lovastatin; Pharmaceutical Preparations; Saccharomyces cerevisiae
PubMed: 33823841
DOI: 10.1186/s12885-021-07963-w -
Current Medicinal Chemistry 2024Previous studies have found a potential role for statins in liver cancer prevention. (Meta-Analysis)
Meta-Analysis
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.
METHODS
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.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Simvastatin; Lovastatin; Liver Neoplasms
PubMed: 37393552
DOI: 10.2174/0929867330666230701000400