6, 8-Diprenylorobol 通过激活细胞内活性氧和 p53 诱导人结肠癌细胞凋亡,Environmental Toxicology

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6, 8-Diprenylorobol 通过激活细胞内活性氧和 p53 诱导人结肠癌细胞凋亡
Environmental Toxicology ( IF 4.4 ) Pub Date : 2020-12-31 , DOI: 10.1002/tox.23093
Yong Jun Choi ₁ , Jongsung Lee ₂ , Sang Hoon Ha ₃ , Han Ki Lee ₄ , Heui Min Lim ₄ , Seon‐Hak Yu ₁ , Chang Min Lee ₁ , Myeong Jin Nam ₄ , Yung‐Hun Yang ₅ , Kyungmoon Park ₁ , Youn Soo Choi _{6,

7} , Kyu Yun Jang _{8,

9,

10} , See‐Hyoung Park ₁

Affiliation

Department of Bio and Chemical Engineering Hongik University Sejong South Korea
Department of Integrative Biotechnology Sungkyunkwan University Suwon South Korea
Division of Biotechnology Jeonbuk National University Iksan South Korea
Department of Biological Science Gachon University Seongnam South Korea
Department of Biological Engineering Konkuk University Seoul South Korea
Department of Biomedical Sciences Seoul National University, Graduate School Seoul South Korea
Department of Medicine College of Medicine, Seoul National University Seoul South Korea
Department of Pathology Jeonbuk National University Medical School Jeonju South Korea
Research Institute of Clinical Medicine of Jeonbuk National University Jeonju South Korea
Biomedical Research Institute of Jeonbuk National University Hospital Jeonju South Korea

6,8-Diprenylorobol 是一种天然化合物，主要存在于 Glycyrrhiza uralensis fisch 和 Maclura tricuspidata，在亚洲传统上被用作食品和药物。到目前为止，尚未研究 6,8-diprenylorobol 在结肠癌中的抗增殖作用。在这项研究中，我们旨在评估 6,8-diprenylorobol 对 LoVo 和 HCT15 这两种人类结肠癌细胞的抗增殖作用。6,8-Diprenylorobol 以剂量和时间依赖性方式抑制 LoVo 和 HCT15 细胞的增殖。40 μM 的 6,8-diprenylorobol 72 小时将两种细胞活力降低到 50% 以下。在 6,8-diprenylorobol（40 和 60 μM）处理 72 小时后，LoVo 和 HCT15 细胞中的晚期凋亡细胞部分分别为 24, 70% 和 13, 90%，这通过检查两种细胞中的 DNA 片段化得到证实. 机械上，6，8-diprenylorobol 激活 p53 及其磷酸化形式（Ser15、Ser20 和 Ser46）表达，但抑制 LoVo 和 HCT15 细胞中的 Akt 和丝裂原活化蛋白激酶 (MAPK) 磷酸化。有趣的是，6,8-diprenylorobol 诱导了细胞内活性氧 (ROS) 的产生，其通过 N-乙酰半胱氨酸 (NAC) 处理减弱。与对照相比，60 μM 6,8-diprenylorobol 导致 LoVo 和 HCT15 中 ROS 水平增加至 210%，而使用 NAC 分别降低至 161% 和 124%。此外，6,8-diprenylorobol 引起的细胞活力和细胞凋亡部分通过与 NAC 孵育而恢复。总之，这些结果表明 6,8-diprenylorobol 通过激活 p53 和生成 ROS 对 LoVo 和 HCT15 结肠癌细胞具有潜在的抗增殖作用。

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6, 8‐Diprenylorobol induces apoptosis in human colon cancer cells via activation of intracellular reactive oxygen species and p53

6,8-Diprenylorobol is a natural compound mainly found in Glycyrrhiza uralensis fisch and Maclura tricuspidata, which has been used traditionally as food and medicine in Asia. So far, the antiproliferative effect of 6,8-diprenylorobol has not been studied yet in colon cancer. In this study, we aimed to evaluate the antiproliferative effects of 6,8-diprenylorobol in LoVo and HCT15, two kinds of human colon cancer cells. 6,8-Diprenylorobol inhibited the proliferation of LoVo and HCT15 cells in a dose- and time-dependent manner. A 40 μM of 6,8-diprenylorobol for 72 h reduced both of cell viability under 50%. After treatment of 6,8-diprenylorobol (40 and 60 μM) for 72 h, late apoptotic cell portion in LoVo and HCT15 cells were 24, 70% and 13, 90%, respectively, which was confirmed by checking DNA fragmentation in both cells. Mechanistically, 6,8-diprenylorobol activated p53 and its phosphorylated form (Ser15, Ser20, and Ser46) expression but suppressed Akt and mitogen-activated protein kinases (MAPKs) phosphorylation in LoVo and HCT15 cells. Interestingly, 6,8-diprenylorobol induced the generation of intracellular reactive oxygen species (ROS), which was attenuated with N-acetyl cysteine (NAC) treatment. Compared to the control, 60 μM of 6,8-diprenylorobol caused to increase ROS level to 210% in LoVo and HCT15, which was reduced into 161% and 124%, respectively with NAC. Furthermore, cell viability and apoptotic cell portion by 6,8-diprenylorobol was recovered by incubation with NAC. Taken together, these results indicate that 6,8-diprenylorobol has the potential antiproliferative effect against LoVo and HCT15 colon cancer cells through activation of p53 and generation of ROS.

更新日期：2020-12-31

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