Abstract
BackgroundStatins 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.MethodsThirty-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.ResultsBaseline 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.ConclusionsFluvastatin 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.
Highlights
Statins are potent and specific inhibitors of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway [1]
Statins have been prescribed for the chronic management of hypercholesterolemia; mounting epidemiological evidence supports a possible role for these drugs in the prevention of advanced prostate cancer (PCa) and improved patient outcomes [2,3,4,5,6,7,8]
We report the results of a pilot window-of-opportunity clinical trial aimed to evaluate the effects of neoadjuvant fluvastatin on markers of cell proliferation and apoptosis in men with localized PCa
Summary
Statins are potent and specific inhibitors of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway [1]. Data from pre-clinical studies have demonstrated that statins can induce tumor-specific apoptosis by directly inhibiting HMGCR in a number of different cancer types, including PCa [9,10,11]. These anti-cancer effects have been attributed to both cholesterol-dependent and -independent mechanisms downstream of HMGCR inhibition [8, 11, 12]. We report the results of a pilot window-of-opportunity clinical trial aimed to evaluate the effects of neoadjuvant fluvastatin on markers of cell proliferation and apoptosis in men with localized PCa. CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Serum and intraprostatic fluvastatin concentrations were quantified by liquid chromatography-mass spectrometry
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