Concurrent blockade of the NF-κB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity
Concurrent blockade of the NF-κB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity
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DOI：
10.1016/j.canlet.2010.02.011
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发表时间：
2010-09-01
期刊：
影响因子：
9.7
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
He, Hai-Ning;Wang, Xia;Lin, Yong
核因子-κ B（NF-κ B）和Akt是两种主要的细胞存活途径，其通常被组成性激活并且可以在癌细胞中被化疗剂进一步刺激。尽管据报道单独靶向NF-κ B或Akt可使癌症治疗增敏，但同时阻断这两种途径使癌细胞对遗传毒性疗法化学增敏的有效性尚未研究。在本研究中，我们研究了两种一线抗癌药物顺铂和依托泊苷在多种癌细胞系中对NF-κ B和Akt通路的激活。检测单独或同时阻断这两种存活途径对顺铂或依托泊苷诱导的细胞毒性的影响。结果显示顺铂和依托泊苷激活癌细胞中的NF-κ B和Akt。用化学抑制剂或siRNA阻断这些途径中的任一个，使癌细胞对顺铂或依托泊苷诱导的细胞毒性中度敏感。引人注目的是，当同时阻断NF-κ B和Akt时，实现了对这些抗癌药物的细胞毒性的更有效的增强。这些数据表明，NF-κ B和Akt协同减弱治疗诱导的细胞毒性，同时阻断这些途径是提高治疗剂抗癌功效的有效策略。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Nuclear factor-kappa B (NF-kappa B) and Akt are two major cell survival pathways that are often constitutively activated and can be further stimulated by chemotherpeutics in cancer cells. Although individually targeting the NF-kappa B or Akt has been reported to sensitize caner therapy, the effectiveness of concurrent blocking these two pathways for chemosensitizing of cancer cells to genotoxic therapeutics has not been investigated. In the present study, we investigate the activation of the NF-kappa B and Akt pathways by two frontline anticancer drugs cisplatin and etopside in a variety of cancer cell lines. The effects of blocking these two survival pathways individually or concurrently on cisplatin- or etopside-induced cytotoxicity were detected. The results show that cisplatin and etopside activate both NF-kappa B and Akt in cancer cells. Blockade of either of these pathways with chemical inhibitors or siRNA moderately sensitized cancer cells to cisplatin-or etopside-induced cytotoxicity. Strikingly, much more effective potentiation of cytotoxicity to these anticancer drugs was achieved when NF-kappa B and Akt were concurrently blocked. These data suggest that NF-kappa B and Akt cooperatively attenuate therapeutic-induced cytotoxicity and concurrently blocking these pathways is an effective strategy for improving the anticancer efficacy of therapeutics. (C) 2010 Elsevier Ireland Ltd. All rights reserved.