Abstract

Uncontrolled regulation of cyclin dependent kinases (CDKs) has negative implications in many cancers and malignancies and has recently led to the approval of select CDK inhibitors. Herein we present data reporting that xanthones, a class of compounds isolated from the purple mangosteen (Garcinia mangostana) fruit, can inhibit CDK2/CyclinE1. We evaluated nine different xanthones, including α-mangostin, β-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C, garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin for toxicity in 22Rν1 (prostate cancer cells) and MDA-MB-231 (breast cancer cells). All compounds dose-dependently inhibited the viability of both cell lines. A cell free biochemical assay was performed to determine if selected phytochemicals inhibited CDK2/CyclinE1. γ-Mangostin and α-mangostin were the strongest inhibitors, respectively. The results suggest that the position of key functional groups including hydroxyl and isoprenyl groups contribute to the CDK2 inhibitory effect. Taken together, the evidence suggests that xanthones can directly target CDK2 providing a possible explanation for their therapeutic potential.

摘要

细胞周期蛋白依赖性激酶 (CDK) 的不受控制的调节对许多癌症和恶性肿瘤具有负面影响，并且最近导致某些 CDK 抑制剂获得批准。在此，我们提供的数据报告说，氧杂蒽酮是从紫色山竹 ( Garcinia mangostana) 中分离的一类化合物) 果实，可抑制 CDK2/CyclinE1。我们评估了九种不同的呫吨酮，包括 α-mangostin、β-mangostin、γ-mangostin、gartanin、8-desoxygartanin、garcinone C、garcinone D、9-hydroxycalabaxanthone 和 3-isomangostin 在 22Rν1（前列腺癌细胞）和 MDA 中的毒性-MB-231（乳腺癌细胞）。所有化合物剂量依赖性地抑制两种细胞系的活力。进行无细胞生化分析以确定所选植物化学物质是否抑制 CDK2/CyclinE1。γ-Mangostin 和 α-Mangostin 分别是最强的抑制剂。结果表明，包括羟基和异戊二烯基在内的关键官能团的位置有助于 CDK2 抑制作用。总之，证据表明氧杂蒽酮可以直接靶向 CDK2，为其治疗潜力提供了可能的解释。