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双氢青蒿素通过 ROS 介导的死亡受体 5 上调增强了载脂蛋白 2L/TRAIL 介导的胰腺癌细胞凋亡。

Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5.

机构信息

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.

出版信息

PLoS One. 2012;7(5):e37222. doi: 10.1371/journal.pone.0037222. Epub 2012 May 30.

DOI:10.1371/journal.pone.0037222
PMID:22666346
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3364248/
Abstract

BACKGROUND

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear.

METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL.

CONCLUSIONS/SIGNIFICANCE: These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.

摘要

背景

青蒿琥酯（DHA）是青蒿素的半合成衍生物，最近在各种癌细胞中显示出抗肿瘤活性。凋亡素 2 配体或肿瘤坏死因子相关凋亡诱导配体（Apo2L/TRAIL）被认为是一种很有前途的抗癌药物，但化学抗性影响了其作为治疗策略的疗效。DHA 和 Apo2L/TRAIL 联合诱导的细胞凋亡尚未得到很好的记录，其涉及的机制仍不清楚。

方法/主要发现：在这里，我们报告 DHA 增强了 Apo2L/TRAIL 治疗胰腺癌的疗效。我们发现，与单独使用药物相比，DHA 和 Apo2L/TRAIL 的联合治疗在体外显著增强了 BxPC-3 和 PANC-1 细胞的凋亡。DHA 的作用是通过生成活性氧、诱导死亡受体 5（DR5）和调节凋亡相关蛋白来介导的。然而，N-乙酰半胱氨酸显著降低了 DHA 和 Apo2L/TRAIL 联合治疗观察到的增强的凋亡。此外，DR5 的小干扰 RNA 敲低也显著降低了 DHA 和 Apo2L/TRAIL 诱导的凋亡量。

结论/意义：这些结果表明，DHA 通过活性氧介导的 DR5 上调增强了 Apo2L/TRAIL 介导的人胰腺癌细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/9547cf3ce236/pone.0037222.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/a5ecba9075bb/pone.0037222.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/bc3fdd45cfbc/pone.0037222.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/b9b4d29d949e/pone.0037222.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/9f0ae0eecb6d/pone.0037222.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/860eb5c3a871/pone.0037222.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/9547cf3ce236/pone.0037222.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/a5ecba9075bb/pone.0037222.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/bc3fdd45cfbc/pone.0037222.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/b9b4d29d949e/pone.0037222.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/9f0ae0eecb6d/pone.0037222.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/860eb5c3a871/pone.0037222.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1d5/3364248/9547cf3ce236/pone.0037222.g006.jpg

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