title: α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth.
abstract: 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.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, 833 South Wood Street, Chicago, IL 60612-7230, USA. jjjohn@uic.edu
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Johnson
authors.forename: Sakina M
authors.initials: SM
authors.lastname: Petiwala
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.forename: John T
authors.initials: JT
authors.lastname: Rasmussen
authors.forename: Vaqar M
authors.initials: VM
authors.lastname: Adhami
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Siddiqui
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Kohl
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005638:Fruit / Q000737:chemistry; D016193:G1 Phase / Q000187:drug effects; D029762:Garcinia mangostana / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011485:Protein Binding / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D044004:Xanthones; D000255:Adenosine Triphosphate; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C021053:mangostin