α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth

• Published in: Carcinogenesis (New York) 2012-02, Vol.33 (2), p.413-419
• Main Authors: Johnson, Jeremy J., Petiwala, Sakina M., Syed, Deeba N., Rasmussen, John T., Adhami, Vaqar M., Siddiqui, Imtiaz A., Kohl, Amanda M., Mukhtar, Hasan
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine Triphosphate - metabolism; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cells, Cultured; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fruit - chemistry; G1 Phase - drug effects; Garcinia mangostana - chemistry; Gynecology. Andrology. Obstetrics; Humans; Inflammation, Microenvironment and Prevention; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Nephrology. Urinary tract diseases; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - prevention & control; Protein Binding - drug effects; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xanthones - pharmacology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr291

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 mm3, while the treatment group had a tumor volume of 410 mm3 (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.