Department of Biological Sciences, College of Biological Science and Biotechnology, and Cancer and Metabolism Institute, Konkuk University, Seoul, Republic of Korea.
Department of Biological Sciences, College of Biological Science and Biotechnology, and.
Clin Cancer Res. 2014 Aug 15;20(16):4302-13. doi: 10.1158/1078-0432.CCR-14-0424. Epub 2014 Jun 17.
The selective killing of tumor cells is an important strategy for cancer therapeutics. The aim of this study was to develop a novel antitumor agent that is safe for normal cells with the ability to selectively target cancer cells.
On the basis of quantitative structure-activity relationship, we synthesized a novel polyphenol conjugate (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23). We evaluated the effect of DPP-23 on proliferation, cell cycle, and apoptosis in various tumor cells. We also assessed molecular targets of DPP-23 using genome-wide expression profiling by DNA microarray and real-time PCR array systems.
DPP-23 effectively inhibited the growth of cancer cells in vitro and in vivo (xenografts in Balb/c nude mice). At a molecular level, DPP-23 targeted the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through the production of reactive oxygen species (ROS) in cancer cells, but not in normal cells, resulting in selective killing of tumor cells via caspase-dependent apoptosis.
The selective generation of ROS in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of ROS in cancer cells.
肿瘤细胞的选择性杀伤是癌症治疗的重要策略。本研究旨在开发一种新型抗肿瘤药物，对正常细胞安全，且具有选择性杀伤癌细胞的能力。
基于定量构效关系，我们合成了一种新型多酚缀合物（E）-3-（3,5-二甲氧基苯基）-1-（2-甲氧基苯基）-2-丙烯-1-酮（DPP-23）。我们评估了 DPP-23 对各种肿瘤细胞增殖、细胞周期和凋亡的影响。我们还使用 DNA 微阵列和实时 PCR 阵列系统的全基因组表达谱评估了 DPP-23 的分子靶标。
DPP-23 有效抑制了体外和体内（Balb/c 裸鼠异种移植）癌细胞的生长。在分子水平上，DPP-23 通过在癌细胞中产生活性氧（ROS）靶向内质网（ER）中的未折叠蛋白反应（UPR），但在正常细胞中不会，导致通过 caspase 依赖性凋亡选择性杀伤肿瘤细胞。
癌细胞中 ROS 的选择性产生可能是选择性杀伤癌细胞的一种有吸引力的策略，同时对正常细胞的细胞毒性可忽略不计。DPP-23 代表了一种有前途的新型治疗剂，可用于癌细胞中 ROS 的选择性产生。
