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Introduction
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate gland, which results from the progressive hyperplasia of stromal and glandular prostatic cells (1). BPH causes increased resistance to urine flow, leading to lower urinary tract symptoms (LUTS) including urinary hesitancy, frequent urination, urgency, thin urine flow and urinary retention (2), which are known to significantly affect the physical and mental health of patients as well as their quality of life. Delayed treatment results in numerous severe complications, such as bleeding from the prostate, recurrent infections, renal stones and even kidney failure.
Although the pathogenesis of BPH remains unclear, the reduction of cell apoptosis, which leads to the increase in the total number of stromal and epithelial cells, has been strongly associated with the development of BPH (3–6). Mitochondrial-dependent pathway is the most common apoptotic pathway in vertebrate animal cells (7–9). The mitochondrial membrane permeabilization, accompanied by the collapse of electrochemical gradient across the mitochondrial membrane, is one of the key events during cellular apoptosis (10). This results in the release of numerous apoptogenic proteins from the mitochondria triggering the activation of aspartate-directed cysteine proteases (caspases) and eventually inducing apoptosis (11–14). Bcl-2 family proteins are key regulators of mitochondria-mediated apoptosis, including anti-apoptotic members such as Bcl-2 and pro-apoptotic members such as Bax (7–9). Mitochondrial outer membrane permeabilization (MOMP) is thought to occur through the formation of pores in the mitochondria by pro-apoptotic Bax-like proteins (15–17), which could be inhibited by anti-apoptotic Bcl-2-like members (7,11,18,19). The ratio of active anti- and pro-apoptotic Bcl-2 family members determines the fate of cells and alteration of the ratio by aberrant expression of these proteins impairs the normal apoptotic program thereby contributing to various apoptosis-related diseases including BPH (20). Therefore, promoting cell apoptosis has been suggested as a promising strategy for the development of anti-BPH agents.
Pharmacotherapy remains the major approach for BPH treatment. The mainstay of pharmacotherapy includes α-adrenergic blockers and 5α-reductase inhibitors (21,22). α-adrenergic blockers inhibit α-adrenergic receptors, relaxing smooth muscle in the prostate and the bladder neck, thus decreasing the blockage of urine flow. 5α-reductase inhibitors suppress 5α-reductase, inhibiting dihydrotestosterone production and, therefore, enlargement of the prostate. However, α-adrenergic blockers and 5α-reductase inhibitors may have serious side-effects such as orthostatic hypotension, decreased libido and ejaculation...