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    • Recent studies revealed that certain plant derived compounds

    2023-01-30

    Recent studies revealed that certain plant-derived compounds can also interfere with AR function. One way of such an interference is by modulating its expression levels. This is the case for the two flavonoids quercetin and luteolin that have been reported to repress the function of AR by inhibiting its protein expression in prostate cancer chenodeoxycholic acid (Xing et al., 2001, Chiu and Lin, 2008). Similarly, guggulsterone, a constituent of the Indian Ayurvedic medicinal plant Commiphora mukul that has been shown to induce apoptosis in cancer cells, affects AR expression by inhibiting its promoter activity. Guggulsterone has been also reported to act as an AR antagonist (Singh et al., 2007). AR decreased expression has been also described as the mechanism for the anti-androgenic effect of resveratrol, a natural stilbene found in grapes and wine, on prostate cancer cells. However, in a recent work, Streicher and his colleagues (Streicher et al., 2014) have demonstrated that resveratrol also inhibits the dimerization of AR, explaining the previously observed disruption in AR-DNA-binding by resveratrol (Harada et al., 2011). On the other hand, emodin, a natural anthraquinone derivative isolated from the roots of Rheum palmatuma, targets AR and suppresses prostate cancer cell growth by inhibiting AR nuclear translocation, due to an increased association of AR with MDM2 and its subsequent enhanced proteasomal degradation (Cha et al., 2005). Modulation of AR function by natural compounds has been also reported to be the result of their direct interaction with AR. This is the case of atraric acid, which binds to AR and blocks ligand induced AR translocation to the nucleus, additionally promoting cellular senescence of prostate cancer cells (Hessenkemper et al., 2014, Papaioannou et al., 2009). Equally, epigallocatechin-3- gallate (EGCG) was found to physically interact with the ligand-binding domain of AR (Siddiqui et al., 2011), inhibiting nuclear AR translocation and protein expression leading to inhibition of prostate cancer cell growth. Analogous action has been described for indole-3-carbinol (I3C), the major active compound in cruciferous vegetables along with its primary digestive derivative, 3,3_-diindolylmethane (DIM) (Le et al., 2003). DIM also exhibits a potent antiproliferative action in prostate cancer cells and was the first identified pure androgen receptor antagonist from plants. Finally, Jones and his colleagues have reported an additional type of AR activity inhibition by the natural compound harmol [the metabolite of harmine, a β-carboline compound naturally found in several medicinal plants including Peganum harmala (Zygophyllaceae) and Banisteriopsis caapi (Malpighiaceae)] (El Gendy et al., 2012, Herraiz et al., 2010). This type of AR inhibition does not involve modulation of ligand binding, but direct binding of the compound to AR in a non-competitive way that prevents normal conformational change of the receptor. The latter renders AR unable for DNA binding and gene expression modulation (Jones et al., 2009).
    Natural agents and membrane initiated androgen actions During the last decades, the mode of action of steroids has been extended: in addition to their classical nuclear transcriptional action, they can also trigger early cell signaling, initiated outside the nucleus and exert also rapid effects. Such actions have been described since 1967 by Szego and Davis, reporting an increase in uterine cAMP within 15 s after iv treatment with physiological doses of 17β-estradiol (Szego and Davis, 1967). This effect was not due to a nuclear transcriptional action, since it was not abrogated by transcription inhibitors. However, progress in this field has been slow until twenty years ago, when evidence accumulated supporting this mode of steroid action. Extra-nuclear steroid actions are characterized by an effect evident in seconds or minutes, an insensitivity to modulators of transcription or translation, evidenced at low, physiological, steroid concentrations and are triggered also by specific membrane-acting, impermeable, steroid analogs (Falkenstein et al., 2000). Androgens exert also extranuclear actions, detected in several cell types and involved in the development, growth, survival, and/or function of cells in different organ systems (osteoblasts, neurons, cardiomyocytes, endothelial, vascular smooth muscle, myometrial, Sertolli cells, spermatozoa, T lymphocytes, breast and prostate cancer). They include binding to specific membrane molecules, signaling cascades activation, rapid ion movements, cytoskeletal rearrangement and modulation of secretion (Kampa and Castanas, 2006, Kampa et al., 2008, Levin, 2008). Nevertheless, the mechanism by which such action of steroids occurs is not properly understood and contrasting reports on this topic have been made (Pelekanou et al., 2013).