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Activation of Caspases-3, -6, and -9 during Finasteride Treatment of Benign Prostatic Hyperplasia

Institut National de la Santé et de la Recherche Médicale (U 407) (A.B., J.A., M.B., C.M.), Faculté de Médecine, Lyon-Sud, 69921 Oullins, France; Service d’Urologie (A.R., M.Dev.), Bat 2F, Centre Hospitalier Lyon-Sud, 69495 Pierre Bénite, France; and Service d’Anatomie et Cytologie Pathologiques (M.Dec.), Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, France

Address all correspondence and requests for reprints to: Dr. Claire Mauduit, Institut National de la Santé et de la Recherche Médicale U 407, Faculté de Médecine Lyon-Sud, BP 12, 69921 Oullins Cedex, France. E-mail: mauduit{at}grisn.univ-lyon1.fr.

Benign prostatic hyperplasia (BPH) results from an increase in both epithelial and stromal compartments of the human prostate. Although inhibitors of 5-reductase such as finasteride have been shown to reduce the size of BPH tissues by inducing apoptosis, their mechanisms of action still remain unknown. The present study supports that such a process triggered by finasteride is caspase dependent with a possible involvement of two effector caspases (caspase-3 and 6) and two initiator caspases (caspase-8 and 9). Indeed, by using tissues from patients affected by BPH and treated by finasteride (5 mg/d) for 2–3, 6–8, or 27–32 d, we observed that the 5-reductase inhibitor induced apoptosis in epithelial cells (evaluated through cell number positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) as early as 2–3 d of treatment, with a maximal activity (250-fold increase, P < 0.0001) at 6–8 d of treatment. However, after 27–32 d of treatment, the number of apoptotic cells was reduced and was close to control. Caspases-3, -6, -8, and -9 were immunolocalized to (basal and secretory) epithelial cells and to a lesser extent to stromal cells. Activated caspase-3 immunoexpression was restricted to epithelial secretory cells, and its immunostaining intensity appeared to be higher in BPH tissues from patients treated for 2–3 or 6–8 d. Consistently, in Western blotting analyses, activated caspases-3 and -6 were detected as early as 2–3 d of treatment in BPH tissues, and their levels were increased after 6–8 d of treatment. In real time quantitative PCR experiments, caspase-3 and -6 mRNA levels were found to be unchanged after finasteride treatment. Activated caspase-8 was not detected in the different conditions tested, whereas activated caspase-9 protein levels were maximally enhanced after 2–3 d of finasteride treatment. In conclusion, we report here that finasteride treatment of BPH tissues induced a caspase-dependent apoptotic process restricted to epithelial cells by activating effector caspases-3 and -6 and exhibited a transient action because the apoptotic process was no longer observed after 27–32 d of treatment.

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