Abstract
Xanthones from the mangosteen are a collection of bioactive compounds derived from the Garcinia mangostana L. The fruit of the mangosteen has been widely studied for its medicinal properties with multiple reports describing its anticancer properties. Despite recent advancements in treatment of prostate cancer, therapeutic resistance driven by the AR-V7 splice variant remains a significant challenge. This review elucidates the ability of mangosteen xanthones to exhibit anti-proliferative and apoptotic activity in prostate cancer models. Mechanistic studies reveal that α-mangostin, the most abundant xanthone in the mangosteen, induce degradation of both AR, AR mutant and AR-V7 helping to overcome therapeutic resistance. Studies show that this AR and AR-V7 degradation is associated with modulation of ER chaperone protein BiP, leading to ubiquitination and proteasomal degradation. α-Mangostin has been shown to activate UPR sensor proteins including PERK, IRE1 and CHOP. Beyond the AR signaling pathway, α-mangostin has been reported to inhibit tumor progression, induce cell cycle arrest, and promote apoptosis via inhibition of cyclin-dependent kinases (CDKs). Preclinical animal studies highlight the efficacy and safety profile of α-mangostin demonstrating prostate tumor inhibition without adverse toxicity on normal cells. Pharmacokinetic parameters indicate that α-mangostin is well tolerated and safe in both preclinical and human clinical trials. In summary, understanding the mechanism of action and identifying direct molecular target of α-mangostin is important for development of novel anti-cancer agents and further clinical studies are required to evaluate its efficacy in chemotherapy.