Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70.
Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70.
复制标题
DOI：
10.1038/cddis.2013.550
复制
发表时间：
2014-01-30
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
Hsp70 通常在癌细胞中过度表达，它所赋予的选择性细胞生存优势可能有助于肿瘤形成过程。因此，对癌细胞中Hsp70水平的药理学控制可能是预防肿瘤进展的有效手段。我们发现布洛芬体外下调 Hsp70 可以增强顺铂对肺癌的抗肿瘤活性。布洛芬显着抑制肺腺癌 A549 细胞中 Hsp70 的表达，并使它们对顺铂敏感，从而增加线粒体凋亡级联反应，而单独的布洛芬不会诱导细胞死亡。布洛芬治疗加速了线粒体破坏上游和下游发生的顺铂依赖性事件。 RNA 干扰消除 Hsp70 导致顺铂诱导的细胞凋亡增加，这证明布洛芬增加的细胞凋亡是由其对 Hsp70 的影响介导的。我们的观察表明，布洛芬对 Hsp70 的抑制通过增强线粒体级联的几个阶段的细胞凋亡来介导对顺铂的敏感性。因此，布洛芬是一种潜在的治疗剂，可以降低顺铂的剂量并限制与其毒性和耐药性发展相关的许多挑战。
Hsp70 is often overexpressed in cancer cells, and the selective cellular survival advantage that it confers may contribute to the process of tumour formation. Thus, the pharmacological manipulation of Hsp70 levels in cancer cells may be an effective means of preventing the progression of tumours. We found that the downregulation of Hsp70 by ibuprofen in vitro enhances the antitumoural activity of cisplatin in lung cancer. Ibuprofen prominently suppressed the expression of Hsp70 in A549 cells derived from lung adenocarcinoma and sensitized them to cisplatin in association with an increase in the mitochondrial apoptotic cascade, whereas ibuprofen alone did not induce cell death. The cisplatin-dependent events occurring up- and downstream of mitochondrial disruption were accelerated by treatment with ibuprofen. The increase in cisplatin-induced apoptosis caused by the depletion of Hsp70 by RNA interference is evidence that the increased apoptosis by ibuprofen is mediated by its effect on Hsp70. Our observations indicate that the suppression of Hsp70 by ibuprofen mediates the sensitivity to cisplatin by enhancing apoptosis at several stages of the mitochondrial cascade. Ibuprofen, therefore, is a potential therapeutic agent that might allow lowering the doses of cisplatin and limiting the many challenge associated with its toxicity and development of drug resistance.