title: Pomegranate extracts impact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo.
abstract: Castration-resistant prostate cancer (CRPC) remains largely dependent on androgen receptor (AR). Residual tissue androgens are consistently detected within CRPC tumors and play a critical role in facilitating AR-mediated signaling pathways which lead to disease progression. Testosterone and dihydrotestosterone (DHT) are the major androgens detected in tumors. They are produced through three biosynthesis pathways: Δ(4), Δ(5), and backdoor pathways. Both androgens bind to and stimulate AR activation. The current study investigates the effects of pomegranate extracts (POM) and their ability to inhibit androgen biosynthesis using PCa cell lines (22RV1 and LNCaP) in vitro as well as the PTEN knockout mouse model representing prostate cancer. Steroids were extracted using ethyl acetate or solid phase extraction, and then analyzed by UPLC/MS/MS. The results showed that POM (0-12μg/mL) reduced the production of testosterone, DHT, DHEA, androstenedione, androsterone, and pregnenolone in both cell lines. In addition our in vivo data supports this observation with a reduction in serum steroids determined after 20 weeks of POM treatment (0.17 g/L in drinking water). In accordance with these results, Western blotting of cell lysates and tPSA analysis determined that PSA was significantly decreased by the treatment of POM. Interestingly, AKR1C3 and AR levels were shown to be increased in both cell lines, perhaps as a negative feedback effect in response to steroid inhibition. Overall, these results provide mechanistic evidence to support the rationale for recent clinical reports describing efficacy of POM in CRPC patients.
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Ming
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Pham
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Deb
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mei Yieng
authors.initials: MY
authors.lastname: Chin
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Kharmate
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Elham Hosseini
authors.initials: EH
authors.lastname: Beheshti
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Locke
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address: eguns@prostatecentre.com.
authors.forename: Emma Tomlinson
authors.initials: ET
authors.lastname: Guns
mesh_terms: D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010936:Plant Extracts / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000728:Androgens; D010936:Plant Extracts; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D017430:Prostate-Specific Antigen
keywords: Androgen biosynthesis; Dihydrotestosterone; Pomegranate extracts; Prostate cancer; Testosterone; UPLC/MS/MS analysis