Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
Drug Discovery and Development Center, Thammasat University, Pathumthani 12121, Thailand.
Life Sci. 2016 May 1;152:60-6. doi: 10.1016/j.lfs.2016.03.038. Epub 2016 Mar 24.
Damnacanthal is an anthraquinone isolated from the root of Morinda citrifolia L. (noni), and it exhibits many pharmacological properties, including anti-cancer activity. Damnacanthal targets several signal transduction proteins related to cell growth inhibition or apoptosis. However, the molecular mechanisms by which damnacanthal affects cell cycle regulation have not been elucidated in detail.
Cyclin D1 is an important regulatory protein in cell cycle progression and is overexpressed in many cancer cells. In this study, we investigated the molecular mechanism of damnacanthal on cyclin D1 expression.
We found that damnacanthal inhibited growth of several cancer cell lines (HCT-116, HT-29, MCF-7 and PC-3) in a dose- and time-dependent manner with a decrease in cyclin D1 protein expression. Damnacanthal did not change mRNA of cyclin D1; rather it suppressed cyclin D1 expression at the post-translational level. Subsequent experiments with several mutant cyclin D1 constructs suggest that the lysine sites of cyclin D1 play a pivotal role in damnacanthal-mediated cyclin D1 degradation. Furthermore, damnacanthal was encapsulated in self-assembled chitosan nanoparticles to improve both physicochemical and biological activities.
Our results suggest that encapsulated damnacanthal exhibits better activity in cell growth inhibition, compared to non-encapsulated damnacanthal. Thus, damnacanthal has potential to be a candidate for the development of chemoprevention or therapeutic agents for cancers.
damnacanthal 是从巴戟天（诺丽）的根部分离得到的蒽醌类化合物，具有多种药理活性，包括抗癌活性。damnacanthal 靶向几种与细胞生长抑制或细胞凋亡相关的信号转导蛋白。然而，damnacanthal 影响细胞周期调控的分子机制尚未详细阐明。
细胞周期蛋白 D1 是细胞周期进程中的重要调节蛋白，在许多癌细胞中过度表达。在这项研究中，我们研究了 damnacanthal 对细胞周期蛋白 D1 表达的分子机制。
我们发现 damnacanthal 以剂量和时间依赖的方式抑制几种癌细胞系（HCT-116、HT-29、MCF-7 和 PC-3）的生长，同时降低细胞周期蛋白 D1 蛋白表达。damnacanthal 不会改变细胞周期蛋白 D1 的 mRNA；相反，它在翻译后水平抑制细胞周期蛋白 D1 的表达。随后用几种突变型细胞周期蛋白 D1 构建体进行的实验表明，细胞周期蛋白 D1 的赖氨酸位点在 damnacanthal 介导的细胞周期蛋白 D1 降解中起着关键作用。此外，damnacanthal 被包裹在自组装壳聚糖纳米粒中，以提高物理化学和生物学活性。
我们的结果表明，与未包裹的 damnacanthal 相比，包裹的 damnacanthal 在抑制细胞生长方面表现出更好的活性。因此，damnacanthal 有可能成为预防或治疗癌症的化学预防剂或治疗剂的候选药物。
