mangostin and Prostatic-Neoplasms

A new anti-cancer drug delivery system, based on gold nanoparticles, has been designed for hydrophobic active compounds. The system is a conjugate of gold/polyethyleneimine (AuNPs/PEI) nanoparticles and sulphated β-cyclodextrin (CD). Anionic cyclodextrin was attached to the positively charged AuNPs/PEI nanoparticles by ionic bonds. Tanshinone IIA and α-mangostin were extracted, purified and encapsulated into the AuNPs/PEI/CD nanoparticles. In vitro preliminary cell viability assays against prostate cancer cell lines PC-3 and DU145 showed that encapsulation resulted in increased cytotoxicity.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cyclodextrins; DNA Fragmentation; Drug Delivery Systems; Gold; Humans; Male; Microscopy, Electron, Transmission; Nanoparticles; Polyethyleneimine; Prostatic Neoplasms; Xanthones

The mangosteen (Garcinia mangostana) fruit has been a popular food in Southeast Asia for centuries and is increasing in popularity in Western countries. We identified α-Mangostin as a primary phytochemical modulating ER stress proteins in prostate cancer cells and propose that α-Mangostin is responsible for exerting a biological effect in prostate cancer cells. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two patients undergoing radical prostatectomy were treated with α-Mangostin and evaluated by RT-PCR, Western blot, fluorescent microscopy and siRNA transfection to evaluate ER stress. Next, we evaluated α-Mangostin for microsomal stability, pharmacokinetic parameters, and anti-cancer activity in nude mice. α-Mangostin significantly upregulated ER stress markers in prostate cancer cells. Interestingly, α-Mangostin did not promote ER stress in prostate epithelial cells (PrECs) from prostate cancer patients. CHOP knockdown enhanced α-Mangostin-induced apoptosis in prostate cancer cells. α-Mangostin significantly suppressed tumor growth in a xenograft tumor model without obvious toxicity. Our study suggests that α-Mangostin is not the only active constituent from the mangosteen fruit requiring further work to understand the complex chemical composition of the mangosteen.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Drug Stability; Endoplasmic Reticulum Stress; Epithelial Cells; Fruit; Garcinia mangostana; Gene Knockdown Techniques; Humans; Male; Mice; Mice, Nude; Microsomes, Liver; Phytotherapy; Prostate; Prostatic Neoplasms; Transcription Factor CHOP; Xanthones; Xenograft Model Antitumor Assays

There is a need to characterize promising dietary agents for chemoprevention and therapy of prostate cancer (PCa). We examined the anticancer effect of α-mangostin, derived from the mangosteen fruit, in human PCa cells and its role in targeting cell cycle-related proteins involved in prostate carcinogenesis. Using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, we found that α-mangostin significantly decreases PCa cell viability in a dose-dependent manner. Further analysis using flow cytometry identified cell cycle arrest along with apoptosis. To establish a more precise mechanism of action, we performed a cell free biochemical kinase assay against multiple cyclins/cyclin-dependent kinases (CDKs) involved in cell cycle progression; the most significant inhibition in the cell free-based assays was CDK4, a critical component of the G1 phase. Through molecular modeling, we evaluated α-mangostin against the adenosine triphosphate-binding pocket of CDK4 and propose three possible orientations that may result in CDK4 inhibition. We then performed an in vivo animal study to evaluate the ability of α-mangostin to suppress tumor growth. Athymic nude mice were implanted with 22Rv1 cells and treated with vehicle or α-mangostin (100 mg/kg) by oral gavage. At the conclusion of the study, mice in the control cohort had a tumor volume of 1190 mm(3), while the treatment group had a tumor volume of 410 mm(3) (P < 0.01). The ability of α-mangostin to inhibit PCa in vitro and in vivo suggests α-mangostin may be a novel agent for the management of PCa.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Cells, Cultured; Cyclin-Dependent Kinase 4; Epithelial Cells; Fruit; G1 Phase; Garcinia mangostana; Humans; Male; Mice; Mice, Nude; Neoplastic Stem Cells; Prostatic Neoplasms; Protein Binding; Xanthones