Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, 833 South Wood Street, Chicago, IL 60612-7230, USA.
Carcinogenesis. 2012 Feb;33(2):413-9. doi: 10.1093/carcin/bgr291. Epub 2011 Dec 9.
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.
需要对有希望用于前列腺癌（PCa）化学预防和治疗的膳食制剂进行特征描述。我们研究了来自山竹果的α-倒捻子素对人前列腺癌细胞的抗癌作用及其在靶向参与前列腺癌发生的细胞周期相关蛋白中的作用。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐测定法，我们发现α-倒捻子素以剂量依赖性方式显著降低 PCa 细胞活力。使用流式细胞术的进一步分析鉴定了细胞周期停滞和细胞凋亡。为了建立更精确的作用机制，我们针对参与细胞周期进程的多个细胞周期蛋白/细胞周期蛋白依赖性激酶（CDK）进行了无细胞生化激酶测定；无细胞测定中最显著的抑制作用是 CDK4，它是 G1 期的关键组成部分。通过分子建模，我们评估了α-倒捻子素对 CDK4 的三磷酸腺苷结合口袋的作用，并提出了可能导致 CDK4 抑制的三种可能取向。然后，我们进行了体内动物研究，以评估α-倒捻子素抑制肿瘤生长的能力。无胸腺裸鼠植入 22Rv1 细胞，并通过口服灌胃给予载体或α-倒捻子素（100mg/kg）。在研究结束时，对照组小鼠的肿瘤体积为 1190mm(3)，而治疗组小鼠的肿瘤体积为 410mm(3)（P<0.01）。α-倒捻子素在体外和体内抑制 PCa 的能力表明，α-倒捻子素可能是管理 PCa 的新型药物。
