Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain

Abstract

Background: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS.

Methods: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed.

Results: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration.

Conclusions: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

Keywords: NADH dehydrogenase [ubiquinone] iron‐sulfur protein 3; benign prostatic hyperplasia; celecoxib/celebrex; finasteride; mitochondrial dysfunction.

FIGURE 1

Impact of Celecoxib and/or Finasteride on NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) in patients with benign prostatic hyperplasia (BPH). Immunostaining of NDUFS3 expression in BPH and normal adjacent prostate (NAP) tissues from prostate cancer patients with incidental BPH. Patients were treated with no drug, celecoxib (Cbx), Finasteride (Fin) or celecoxib plus Finasteride (Cbx + Fin) for 28 days before surgery. (A) Representative images showing the expression of NDUFS3 (brown) in NAP and BPH tissues. Scale bars indicate 500 μm. (B) Representative images showing the expression of NDUFS3 (brown) in BPH. Scale bars indicate 200 μm, bottom inset 50 μm. (C) Quantification of mean epithelial NDUFS3 staining H-Score. (D) Quantification of mean stromal NDUFS3 staining H-Score. Data represent mean ± S.D.; *, p<0.05; **, p<0.01; ns, nonsignificant. Number of patients indicated in parentheses.

FIGURE 2

Impact of celecoxib and/or Finasteride on inflammatory cells in patients with benign prostatic hyperplasia (BPH). Quantification of CD20+ B-cells, CD68+ macrophages, and CD4+ and CD8+ T-cells in BPH tissues the prostate from prostate cancer patients with incidental BPH. Patients were treated with no drug, celecoxib (Cbx), Finasteride (Fin) or celecoxib plus Finasteride (Cbx + Fin) for 28 days before surgery. (A) Representative images showing CD20 (brown) or CD68 (red) inflammatory cells in BPH tissues. (B) Representative images showing CD4 (brown) and CD8 (red) inflammatory cells in BPH tissues. (C) Quantitation of mean number of CD20+, and (D) CD68+ cells expressed as a percentage of positively stained cells. (E) Quantitation of mean number of CD4 and CD8+ cells per 20× field. (F) Quantification of overall inflammation score. Scale bars indicate 100 μm. Data represent mean ± S.D. Number of patients indicated in parentheses.

FIGURE 3

Impact of Celecoxib on NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) in murine prostate. Immunostaining of NDUFS3 expression in murine prostate. Male mice were treated with celecoxib (Cbx) or vehicle control for 28 days. (A) Representative images showing the expression of NDUFS3 (brown) in the ventral, lateral, dorsal, and anterior prostate lobes of Control and celecoxib-treated mice. Scale bars indicate 200 μm. (B) Quantitation of mean epithelial NDUFS3 staining H-Score. (C) Quantitation of mean stromal NDUFS3 staining H-Score. (D) Intense NDUFS3 staining (black arrows) was observed in some basal epithelial cells of untreated mice, and these were absent in celecoxib treated mice. Scale bars indicate 50 μm. Data represent mean ± S.D.; *p < 0.05**p < 0.01****p < 0.0001. ns, nonsignificant. ap, anterior prostate; dp, dorsal prostate; lp, lateral prostate; vp, ventral prostate.

FIGURE 4

Impact of Celecoxib on inflammatory cells in murine prostate. Quantification of CD68+ macrophages, and CD3+ T-cells, and CD19+ B-cells in male mice treated with celecoxib (Cbx) or vehicle control for 28 days. (A) Quantitation of mean number of CD68+ cells in the ventral, lateral, dorsal and anterior prostate lobes of Control and celecoxib-treated mice. (B) Representative images showing CD68 (brown) macrophages in the murine prostate. (C) Quantitation of mean number of CD3+ cells. (D) Representative images showing CD3+ cells (brown). (E) Quantitation of the mean number of CD19+ cells in murine prostate. (F) Representative images showing CD19+ cells (brown). Scale bars indicate 100 μm. Data represent mean ± S.D. Number of mice indicated in parentheses. ap, anterior prostate; dp, dorsal prostate; lp, lateral prostate; vp, ventral prostate.