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硫酸黏菌素增强 TRAIL 对神经胶质瘤细胞系的细胞毒性作用。

Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines.

机构信息

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

出版信息

PLoS One. 2014 Apr 16;9(4):e94438. doi: 10.1371/journal.pone.0094438. eCollection 2014.

DOI:10.1371/journal.pone.0094438
PMID:24740347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3989199/
Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.

摘要

肿瘤坏死因子相关凋亡诱导配体（TRAIL）已被报道在癌症治疗中具有治疗活性。然而，许多肿瘤仍然对 TRAIL 治疗具有抗性。因此，能够增强 TRAIL 细胞毒性作用的小分子可用于联合治疗。在这里，我们发现离子载体抗生素盐霉素与 TRAIL 协同作用，增强了胶质母细胞瘤细胞中 TRAIL 诱导的细胞凋亡。低剂量盐霉素与 TRAIL 联合治疗可增强 caspase-3 的激活，并增加 TRAIL-R2 细胞表面表达。TRAIL-R2 的上调对于介导盐霉素对 TRAIL 介导的细胞凋亡的刺激作用是必需的，因为它被 siRNA 介导的 TRAIL-R2 敲低所阻断。盐霉素与 TRAIL 协同作用在裸鼠异种移植的人胶质母细胞瘤细胞中表现出明显的抗肿瘤作用。我们的结果表明，TRAIL 和盐霉素的联合应用可能是克服胶质母细胞瘤细胞中 TRAIL 抗性的有用工具，并且可能代表治疗这些肿瘤的潜在药物。重要的是，盐霉素+TRAIL 能够诱导明确的胶质母细胞瘤干细胞样系的细胞死亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/e8d252609699/pone.0094438.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/2c1dd4423ef3/pone.0094438.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/d16c3279da5a/pone.0094438.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/9df4e68a8334/pone.0094438.g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/93c5091770a6/pone.0094438.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/ba146503189d/pone.0094438.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/4f80c9c8653e/pone.0094438.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/f949246bd282/pone.0094438.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/649eec78aea0/pone.0094438.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/e8d252609699/pone.0094438.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/2c1dd4423ef3/pone.0094438.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/d16c3279da5a/pone.0094438.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/9df4e68a8334/pone.0094438.g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/93c5091770a6/pone.0094438.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/ba146503189d/pone.0094438.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/4f80c9c8653e/pone.0094438.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/f949246bd282/pone.0094438.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/649eec78aea0/pone.0094438.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00a4/3989199/e8d252609699/pone.0094438.g010.jpg

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