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11-去氢表雄甾二酮内酯通过线粒体紊乱和内质网应激通路诱导人黑素瘤细胞凋亡。

Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells.

机构信息

Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan.

Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan.

出版信息

Mar Drugs. 2012 Aug;10(8):1883-1898. doi: 10.3390/md10081883. Epub 2012 Aug 22.

DOI:10.3390/md10081883
PMID:23015779
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3447343/
Abstract

In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis-inducing activities against A2058 melanoma cells. Anti-tumor effects of 11-dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2-8 μg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11-dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress-mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress-mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways.

摘要

在这项研究中,从软珊瑚 Sinularia leptoclados 中分离得到的单体化合物 11-脱水辛可尼醇内酯对 A2058 黑色素瘤细胞具有抗增殖、抗迁移和诱导凋亡的活性。通过 MTT 测定、细胞迁移测定和流式细胞术测定了 11-脱水辛可尼醇内酯的抗肿瘤作用。2-8μg/ml 的 11-脱水辛可尼醇内酯可剂量依赖性地抑制黑色素瘤细胞的生长和迁移。流式细胞术数据表明,11-脱水辛可尼醇内酯诱导黑色素瘤细胞发生早期和晚期凋亡。研究发现,11-脱水辛可尼醇内酯诱导的凋亡与通过 caspase 依赖性途径的线粒体介导的凋亡有关,这是通过线粒体膜电位(∆Ψm)丧失、细胞色素 C 释放、caspase-3/-9 和 Bax 的激活以及 Bcl-2/Bcl-xL 的抑制来阐明的。PARP-1 的裂解表明部分涉及 caspase 非依赖性途径。免疫印迹数据显示 PERK/eIF2α/ATF4/CHOP 和 ATF6/CHOP 的上调与内质网应激伴侣 GRP78、GRP94、钙连蛋白、钙网蛋白和 PDIA 的升高相关,表明这些因素参与了 11-脱水辛可尼醇内酯诱导的内质网应激介导的凋亡。用 salubrinal 预处理后凋亡事件的消除表明,内质网应激介导的凋亡也是 11-脱水辛可尼醇内酯对黑色素瘤细胞的诱导作用。本研究数据表明,11-脱水辛可尼醇内酯可能通过线粒体失调和内质网应激途径诱导黑色素瘤细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/75008978b287/marinedrugs-10-01883-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/92fa1f19dbae/marinedrugs-10-01883-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/c8008c53b054/marinedrugs-10-01883-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/9a076284af02/marinedrugs-10-01883-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/5a56afeb1b6a/marinedrugs-10-01883-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/75008978b287/marinedrugs-10-01883-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/92fa1f19dbae/marinedrugs-10-01883-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/c8008c53b054/marinedrugs-10-01883-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/9a076284af02/marinedrugs-10-01883-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/5a56afeb1b6a/marinedrugs-10-01883-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5ef/3447343/75008978b287/marinedrugs-10-01883-g005.jpg

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