(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Prostatic-Neoplasms

Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors.. OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO. 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT.. exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.

Topics: Animals; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Oxygen; Oxygen Consumption; Prostatic Neoplasms; Simvastatin; Superoxides; Tumor Hypoxia

To assess the role of multi-parametric MRI (mpMRI) in assessment of tumor response to fluvastatin administered prior to radical prostatectomy.. Men with MRI-visible, clinically significant prostate cancer and due to be treated with radical prostatectomy were prospectively enrolled. mpMRI was performed at baseline and following 6-7 week of neoadjuvant oral statin therapy (40 mg fluvastatin, twice daily), prior to prostatectomy. MRI assessment included tumor size, T2 relaxation time, ADC value, K-trans (volume transfer constant), Kep (reflux constant), and Ve (fractional volume) parameters at the 2 time points. Initial prostate needle biopsy cores, prior to starting oral statin therapy, corresponding to site of tumor on radical prostatectomy specimens were selected for analysis. The effect of fluvastatin on tumor proliferation (marker Ki67) and on tumor cell apoptosis (marker cleaved Caspase-3, CC3) were analyzed and correlated with MRI findings.. Nine men with paired MRI studies were included in the study. Binary histopathological data was available for 6 of the participants. No significant change in tumor size (. mpMRI techniques may not be sufficiently sensitive to detect the types (or magnitude) of tumor cell changes observed following 6-7 weeks of fluvastatin therapy for prostate cancer.

Topics: Administration, Oral; Aged; Evaluation Studies as Topic; Fluvastatin; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pilot Projects; Prospective Studies; Prostate; Prostatic Neoplasms; Treatment Outcome

Fluvastatin (FLV) is known to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is over-expressed in various cancers. FLV has been reported to decrease cancer development and metastasis. However, because of low bioavailability, extensive first-pass metabolism and short half-life of FLV (1.2 h), it is not appropriate for clinical application. Therefore, FLV-loaded emulsomes were formulated and optimized using Box-Behnken experimental design to achieve higher efficiency of formulation. Antitumor activity of optimized FLV-loaded emulsomes was evaluated in prostate cancer cells using cell cytotoxicity, apoptotic activity, cell cycle analysis, and enzyme-linked immunosorbent assay. The FLV-loaded emulsomes exhibited a monodispersed size distribution with a mean particle size less than 100 nm as measured by zetasizer. The entrapment efficiency was found to be 93.74% with controlled drug release profile. FLV-EMLs showed a significant inhibitory effect on the viability of PC3 cells when compared to the free FLV (P < 0.0025). Furthermore, FLV-EMLs showed significant arrest in G2/M and increase in percentage of apoptotic cells as compared to free FLV. FLV-EMLs were more effective than free FLV in reducing mitochondrial membrane potential and increase in caspase-3 activity. These results suggesting that FLV-EMLs caused cell cycle arrest which clarifies its significant antiproliferative effect compared to the free drug. Therefore, optimized FLV-EMLs may be an effective carrier for FLV in prostate cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Cytotoxins; Delayed-Action Preparations; Drug Carriers; Fluvastatin; Humans; Male; Particle Size; PC-3 Cells; Prostatic Neoplasms

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Epidemiological and pre-clinical evidence support an association between statin use and delayed prostate cancer (PCa) progression. Here, we evaluated the effects of neoadjuvant fluvastatin treatment on markers of cell proliferation and apoptosis in men with localized PCa.. Thirty-three men were treated daily with 80 mg fluvastatin for 4-12 weeks in a single-arm window-of-opportunity study between diagnosis of localized PCa and radical prostatectomy (RP) (ClinicalTrials.gov: NCT01992042). Percent Ki67 and cleaved Caspase-3 (CC3)-positive cells in tumor tissues were evaluated in 23 patients by immunohistochemistry before and after treatment. Serum and intraprostatic fluvastatin concentrations were quantified by liquid chromatography-mass spectrometry.. Baseline characteristics included a median prostate-specific antigen (PSA) level of 6.48 ng/mL (IQR: 4.21-10.33). The median duration of fluvastatin treatment was 49 days (range: 27-102). Median serum low-density lipoprotein levels decreased by 35% after treatment, indicating patient compliance. Median PSA decreased by 12%, but this was not statistically significant in our small cohort. The mean fluvastatin concentration measured in the serum was 0.2 μM (range: 0.0-1.1 μM), and in prostatic tissue was 8.5 nM (range: 0.0-77.0 nM). At these concentrations, fluvastatin induced PCa cell death in vitro in a dose- and time-dependent manner. In patients, fluvastatin treatment did not significantly alter intratumoral Ki67 positivity; however, a median 2.7-fold increase in CC3 positivity (95% CI: 1.9-5.0, p = 0.007) was observed in post-fluvastatin RP tissues compared with matched pre-treatment biopsy controls. In a subset analysis, this increase in CC3 was more pronounced in men on fluvastatin for >50 days.. Fluvastatin prior to RP achieves measurable drug concentrations in prostatic tissue and is associated with promising effects on tumor cell apoptosis. These data warrant further investigation into the anti-neoplastic effects of statins in prostate tissue.

Topics: Aged; Apoptosis; Biomarkers, Tumor; Caspase 3; Disease Progression; Fluvastatin; Humans; Hydroxymethylglutaryl CoA Reductases; Ki-67 Antigen; Male; Middle Aged; Neoadjuvant Therapy; Pilot Projects; Preoperative Care; Prostatectomy; Prostatic Neoplasms

The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.. Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry.. High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.. Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Dipyridamole; Drug Repositioning; Fluvastatin; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Male; Mevalonic Acid; Mice; Mice, Inbred NOD; Mice, SCID; Prostatic Neoplasms; Sterol Regulatory Element Binding Protein 2; Sterols; Xenograft Model Antitumor Assays

Statins are commonly used in the middle-aged and elderly people for treatment of hyperlipidemia. Both alpha lipoic acid (ALA) and ellagic acid (EA) are natural antioxidants found in a normal diet. They can protect against cellular damage and induce cellular apoptosis in many types of cancer cells. Fluvastatin (FLV) was combined with ALA and EA in a nanostructured lipid carrier (NLC) formula. The prepared NLCs were imaged with a transmission electron microscope (TEM). Particle size and zeta potential and FLV entrapment efficiency (%EE) were measured, and the FLV release profile was constructed. Cellular viability, caspase-3 enzyme levels, and cellular cycle were analyzed. The prepared NLCs were spherical, with a size of 85.2 ± 4.1 nm, and had a zeta potential of - 25.1 ± 3.4 mV and a %EE of 98.2 ± 1.1%. FLV IC

Topics: Drug Carriers; Ellagic Acid; Fluvastatin; Humans; Male; Nanostructures; PC-3 Cells; Prostatic Neoplasms; Thioctic Acid

Although prostate cancer is commonly diagnosed, few risk factors for high-grade prostate cancer are known and few prevention strategies exist. Statins have been proposed as a possible treatment to prevent prostate cancer.. Using electronic and administrative files from the Veterans Affairs New England Healthcare System, we identified 55,875 men taking either a statin or antihypertensive medication. We used age- and multivariable-adjusted Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence among patients taking statins (n = 41,078) compared with patients taking antihypertensive medications (n = 14,797). We performed similar analyses for all lipid parameters including total cholesterol examining each lipid parameter as a continuous variable and by quartiles. All statistical tests were two-sided.. Compared with men taking an antihypertensive medication, statin users were 31% less likely (HR = 0.69, 95% CI = 0.52 to 0.90) to be diagnosed with prostate cancer. Furthermore, statin users were 14% less likely (HR = 0.86, 95% CI = 0.62 to 1.20) to be diagnosed with low-grade prostate cancer and 60% less likely (HR = 0.40, 95% CI = 0.24 to 0.65) to be diagnosed with high-grade prostate cancer compared with antihypertensive medication users. Increased levels of total cholesterol were also associated with both total (HR = 1.02, 95% CI = 1.00 to 1.05) and high-grade (HR = 1.06, 95% CI = 1.02 to 1.10) prostate cancer incidence but not with low-grade prostate cancer incidence (HR = 1.01, 95% CI = 0.98 to 1.04).. Statin use is associated with statistically significantly reduced risk for total and high-grade prostate cancer, and increased levels of serum cholesterol are associated with higher risk for total and high-grade prostate cancer. These findings indicate that clinical trials of statins for prostate cancer prevention are warranted.

Topics: Aged; Aged, 80 and over; Anticarcinogenic Agents; Anticholesteremic Agents; Antihypertensive Agents; Atorvastatin; Biomarkers, Tumor; Cholesterol; Confounding Factors, Epidemiologic; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Indoles; Lipids; Lovastatin; Male; Middle Aged; Multivariate Analysis; New England; Pravastatin; Proportional Hazards Models; Prostatic Neoplasms; Pyrroles; Risk Assessment; Severity of Illness Index; Simvastatin; Veterans

Recent data suggest that statin use may be associated with a reduced risk of advanced prostate cancer. However, the influence of statins on prostate-specific antigen (PSA) levels and what effect this could potentially have on prostate cancer diagnosis are unknown.. We conducted a longitudinal study of 1214 men who were prescribed a statin between 1990 and 2006 at the Durham Veterans Affairs Medical Center who were free of prostate cancer, had not undergone prostate surgery or taken medications known to alter androgen levels and who had at least one PSA value within 2 years before and at least one PSA value within 1 year after starting a statin. The change in PSA from before to after statin treatment was analyzed as a continuous variable using the Wilcoxon signed rank test. The association between change in PSA and change in cholesterol parameters (low-density lipoprotein [LDL], high-density lipoprotein [HDL], and total cholesterol) was analyzed using multivariate linear regression. All statistical tests were two-sided.. Mean (SD) age when starting statins was 60.3 (8.3) years; median prestatin PSA concentration was 0.9 (1.9) ng/mL; and mean prestatin LDL cholesterol concentration was 144 (34) mg/dL. After starting a statin, the median LDL decline was 27.5%, and the median PSA decline was 4.1% (P < .001, for both comparisons). Changes in PSA concentration were strongly associated with statin dose and changes in LDL levels. For every 10% decrease in LDL after starting a statin, PSA levels declined by 1.64 (95 % confidence interval [CI] = 0.64% to 2.65%, p = .001). Among men most likely to be under consideration for prostate biopsy (prestatin PSA levels > or =2.5 ng/mL, n = 188), those with >41% declines in LDL (highest quartile) after starting a statin experienced a 17.4% (95% CI = 10.0% to 24.9%) decline in serum PSA.. PSA levels declined by a statistically significant extent after initiation of statin treatment. The reduction was most pronounced among men with the largest LDL declines and those with PSA levels that would make them candidates for prostate biopsy. By lowering PSA levels, statins may complicate cancer detection, although further studies are needed to quantify the clinical significance of this effect.

Topics: Aged; Atorvastatin; Biomarkers, Tumor; Cholesterol, HDL; Cholesterol, LDL; Early Diagnosis; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Indoles; Linear Models; Longitudinal Studies; Lovastatin; Male; Middle Aged; Multivariate Analysis; Pravastatin; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrroles; Risk Assessment; Simvastatin; Veterans

To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro.. The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic.. Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied.. Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cytoplasm; Deoxycytidine; Diphosphonates; DNA Fragmentation; Drug Antagonism; Drug Synergism; Epirubicin; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gemcitabine; Humans; Imidazoles; Indoles; Lung Neoplasms; Male; Prostatic Neoplasms; Zoledronic Acid

This is the largest and longest clinical study to date to examine statin usage and overall patient survival following clinically localized prostate cancer. In a retrospective examination of 938 consecutive patients with early-stage prostate cancer treated with brachytherapy, 191 patients were documented to be taking statin medications. The patients taking statin medications had significantly lower prostate-specific antigen values, percent positive biopsies, and prostate volume than those patients not taking statin medications. Statin usage resulted in a nonstatistical improvement in all survival parameters with the results most pronounced for atorvastatin. Improving prostate cancer survival with statins could have important treatment implications and could potentially limit or even improve the role of supplemental therapies. A prospective trial of statin medications in conjunction with definitive local treatment for prostate cancer is recommended.

Topics: Aged; Atorvastatin; Biopsy; Brachytherapy; Cause of Death; Chemotherapy, Adjuvant; Chi-Square Distribution; Disease-Free Survival; Fatty Acids, Monounsaturated; Fluvastatin; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Male; Neoplasm Staging; Pravastatin; Proportional Hazards Models; Prostatic Neoplasms; Pyrroles; Retrospective Studies; Simvastatin; Survival Analysis

Members of the statin family of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors are being investigated for the therapy and prevention of cancers because of their growth-inhibitory effects on epithelial cells. Some epidemiologic studies show that patients taking statins show a lower incidence of cancer compared with those taking other cholesterol-lowering medication. In contrast, other studies show that statin use does not correlate with cancer risk. To address this discrepancy, we investigated the efficacy of different statins on the PC-3 prostate cancer cell line and the androgen-dependent LNCaP prostate cancer cell line. Clinically used statins, lovastatin, fluvastatin, and simvastatin inhibit proliferation of the two prostate cancer cells by inducing a G1 arrest. Lovastatin induced the arrest at 0.5 micromol/L, a concentration easily reached in the serum after oral administration. Pravastatin, however, was less effective at inhibiting 3-hydroxy-3-methylglutaryl CoA reductase in PC-3 cells and had to be present at 200 times higher concentrations to effect a cell cycle arrest. Another potential source of variability is the different levels of the cyclin-dependent kinase (cdk) inhibitor p27 noted in prostate cancers particularly because statins have been suggested to act through the induction of cdk inhibitors. All three statins (lovastatin, fluvastatin, and simvastatin) inhibited cyclin E/cdk2 kinase leading to hypophosphorylation of Rb, but this inhibition was correlated with a loss of the activating phosphorylation on Thr160 of cyclin E-associated cdk2 and not dependent on the cdk inhibitors p21 and p27. Therefore, p27 status is unlikely to confound the epidemiologic data on the efficacy of statins in prostate cancer. To make definitive conclusions about the efficacy of statins on cancer prevention, however, the epidemiologic studies should take into account the type of statin used and the serum concentrations achieved and ensure that the tested statin inhibits the specific type of cancer in vitro at those concentrations.

Topics: Cell Cycle; Cell Line, Tumor; Cyclin E; Cyclin-Dependent Kinase 2; Fatty Acids, Monounsaturated; Fluvastatin; G1 Phase; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Male; p21-Activated Kinases; Phosphorylation; Pravastatin; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Simvastatin