Apoptosis Immune receptor Inflammation Mesothelioma Therapy
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摘要

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.

译文

Toll 样受体 3 (TLR3) 是一种免疫受体,其行为类似于肿瘤细胞中的死亡受体,从而为癌症治疗提供了一个原始目标。针对恶性间皮瘤 (一种侵袭性和不可治愈的胸膜和腹膜肿瘤) 的 tlr2 的治疗潜力迄今尚未得到解决。我们研究了人间皮瘤细胞系的 TLR3 表达和对合成的 dsRNA Poly (I: C) 的敏感性,单独或与间皮瘤的金标准化疗的铂联合。通过 Poly (I: C) 激活 tlr2 诱导 4/8 TLR3-positive 细胞株的凋亡,但不诱导 TLR3-negative 细胞株的凋亡。联合使用的顺铂/Poly (I: C) 治疗增强了 3/4 Poly (I: C) 敏感细胞系的凋亡,克服了对 Poly (I: C) 的耐药性或者在 2/4 个细胞系中单独使用顺铂。联合治疗的疗效依赖于顺铂诱导的 c-FLIP 的下调,c-FLIP 是外源性凋亡途径的主要调节因子,导致 caspase-8-mediated 途径的增强。值得注意的是,从腹膜间皮瘤患者中分离出的 6/6 个原代细胞样本表达了 tlr4。患者来源的细胞对 Poly (I: C) 单独敏感,而联合顺铂/Poly (I: C) 治疗诱导显著的细胞死亡。我们的研究结果表明,针对 tlr2 与顺铂的联合应用为间皮瘤提供了一种创新的治疗策略。

Cisplatin

呼吸 铂类抗肿瘤药 药物
概述  :  

药物概述 顺铂为铂类抗肿瘤药,干扰 DNA 复制或与核蛋白及胞浆白结合。本品主要由肾排泄。腹腔内注射后腔内器官浓度为静脉注药的2.5~8.0倍。   适应证 本品为治疗多种实体瘤的一线用药。与 VP-16(足叶乙苷)联合为治疗小细胞肺癌和非小细胞肺癌一线方案。本品为化疗增敏剂,目前国外广泛用于Ⅳ期不能手术的非小细胞肺癌的局部放疗,可提高疗效及改善生存期。   剂型与特征 注射剂。本品只能

Cisplatin   /sis'plætən/

释    义   n. 铂化合物,顺铂

例    句   Cisplatin and other platinum-based cancer drugs destroy tumor cells by binding to DNAstrands, interfering with DNA replication. 顺铂和其他以铂为基础的癌症药物通过靶定DNA链,干扰DNA复制而破坏肿瘤细胞。

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