title: Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro.
abstract: Castration resistant prostate cancer (CRPC) is often lethal and inevitably develops after androgen ablation therapy. However, in the majority of cases it remains androgen dependent. CRPC tumors have the ability to synthesize their own androgens from cholesterol by engaging in de novo steroidogenesis. We investigated the potential of 22RV1 prostate cancer cells to convert the supplemented steroid precursors within this pathway under the effects of current clinical steroidogenesis inhibitors such as abiraterone and dutasteride, either alone or in combination. Under steroid starved conditions, enzymes responsible for de novo steroidogenesis were upregulated. Testosterone and dihydrotestosterone (DHT) were formed by using both dehydroepiandrosterone (DHEA) and progesterone as substrates. Formation of testosterone and DHT was higher following incubation with DHEA compared to progesterone. Progesterone decreased the mRNA expression of enzymes responsible for steroidogenesis. Abiraterone treatment decreased testosterone production but increased several precursor steroids in both classical and backdoor pathways in the presence of progesterone. In contrast, the DHT levels were elevated following treatment with abiraterone when progesterone was absent. Dutasteride decreased the formation of testosterone, DHT and precursor steroids in the backdoor pathway but increased steroid precursors in the classical steroidogenesis pathway. The combination of abiraterone and dutasteride decreased testosterone and DHT in the presence of progesterone but increased DHT in the absence of progesterone. Abiraterone inhibited androgen receptor (AR) activation but not to the same extent as MDV3100. However, abiraterone and dutasteride treatment, either alone or in combination, were more effective in decreasing prostate specific antigen secretion into the media than MDV3100. Thus, while interventions with these drugs alone or in combination fail to completely inhibit steroidogenesis in the 22RV1 cells, the combined inhibition of androgen production and blockade of AR can exceed the effect of MDV3100. Further characterization of bypass mechanisms that may develop as a response to these inhibitors is necessary to achieve optimal suppression of testosterone and DHT synthesis as a part of therapeutic regimens for the treatment of CRPC.
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Pham
authors.affiliation: Department of Biopharmaceutical Sciences, Roosevelt University College of Pharmacy, Schaumburg, IL 60173, USA.
authors.forename: Subrata
authors.initials: S
authors.lastname: Deb
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Dong Sheng
authors.initials: DS
authors.lastname: Ming
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Elham
authors.initials: E
authors.lastname: Hosseini-Beheshti
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address: eguns@prostatecentre.com.
authors.forename: Emma S Tomlinson
authors.initials: ES
authors.lastname: Guns
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism*; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology*; D001378:Azasteroids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D000068538:Dutasteride; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors; D011374:Progesterone / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D001378:Azasteroids; D011944:Receptors, Androgen; D003687:Dehydroepiandrosterone; D011374:Progesterone; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C089740:abiraterone; D000068538:Dutasteride
keywords: Abiraterone; Androgen ablation; Androgen blockade; Androgen deprivation; CYP17A1; Castration resistant Prostate cancer; De novo steroidogenesis; Dutasteride; SRD5A1; SRD5A2