20(S)-protopanaxadiol regio-selectively targets androgen receptor: anticancer effects in castration-resistant prostate tumors
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Mohamed Ben-Eltriki1,2, Subrata Deb5, Mohamed Hassona1, Gray Meckling1, Ladan Fazli1,3, Mei Yieng Chin1, Nada Lallous1, Takeshi Yamazaki1, William Jia4, Paul S. Rennie1,3, Artem Cherkasov1 and Emma S. Tomlinson Guns1,3
1The Vancouver Prostate Centre at Vancouver General Hospital, Vancouver, BC, Canada
2Department of Experimental Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
3Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
4Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada
5Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USA
Emma S. Tomlinson Guns, email: firstname.lastname@example.org
Keywords: 20(S)-protopanaxadiol ginsenoside; androgen receptor; apoptosis; castration resistant prostate cancer
Received: August 25, 2017 Accepted: February 24, 2018 Published: April 20, 2018
We have explored the effects of 20(S)-protopanaxadiol (aPPD), a naturally derived ginsenoside, against androgen receptor (AR) positive castration resistant prostate cancer (CRPC) xenograft tumors and have examined its interactions with AR. In silico docking studies for aPPD binding to AR, alongside transactivation bioassays and in vivo efficacy studies were carried out in the castration-resistant C4-2 xenograft model. Immunohistochemical (IHC) and Western blot analyses followed by evaluation of AR, apoptotic, cell cycle and proliferative markers in excised tumors was performed. The growth of established CRPC tumors was inhibited by 53% with aPPD and a corresponding decrease in serum PSA was seen compared to controls. The IHC data revealed that Ki-67 was significantly lower for aPPD treated tumors and was associated with elevated p21 and cleaved caspase-3 expression, compared to vehicle treatment. Furthermore, aPPD decreased AR protein expression in xenograft tumors, while significantly upregulating p27 and Bax protein levels. In vitro data supporting this suggests that aPPD binds to and significantly inhibits the N-terminal or the DNA binding domains of AR. The AR androgen binding site docking score for androgen (dihydrotestosterone) was -11.1, while that of aPPD was -7.1. The novel findings described herein indicate aPPD potently inhibits PCa in vivo partly via inhibition of a site on the AR N-terminal domain. This manifested as cell cycle arrest and concurrent induction of apoptosis via an increase in Bax, cleaved-caspase-3, p27 and p21 expression.
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