Xanthones from Mangosteen (Garcinia mangostana) Promote Androgen Receptor Degradation in Prostate Cancer

Prostate cancer may seemingly be a non-issue to many men, as multiple drugs are approved for the treatment of prostate cancer and its five-year survival rates are encroaching on 100%. However, this statistic excludes the 5% of patients that are identified to have distant (metastasized) prostate cancer or who have developed castration resistant prostate cancer, both of which have a five-year survival rate of only about 30%. The striking contrast in these survival rates highlights the large void in prostate cancer therapies available for advanced cases. The most popular treatment for prostate cancer is anti-androgen drugs, which are androgen receptor antagonists and disrupt androgen signaling. However, anti-androgens cannot pharmacologically inhibit the androgen receptor in castration resistant prostate cancer, where mutant forms of the androgen receptor drive cancer independently by transcribing their own sets of genes and by mutating in response to initial drug treatment. These studies report on the anti-prostate cancer activities of xanthones isolated from the purple mangosteen, Garcinia mangostana. Cyclin dependent kinases 2 and 4 were identified as targets of mangosteen xanthones through cell-free inhibition assays and in vitro analyses of downstream targets. Moreover, α-mangostin effectively decreases prostate cancer cell viability by promoting apoptosis and by promoting the degradation of wild-type and mutant androgen receptor. Mechanistic studies revealed that α-mangostin activates a cell stress and chaperone protein, BiP, binds to BiP protein itself, and promotes an interaction between the androgen receptor and BiP in prostate cancer cells. Finally, α-mangostin had significant antitumor activity and decreased the expressions of wild type and mutant androgen receptor in vivo. This dissertation summarizes these findings and shows that androgen receptor degradation may be an effective strategy for treating castration resistant prostate cancer, which has large implications for the future of prostate cancer targeted therapies.