TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells.
TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells.
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DOI：
10.1038/srep32737
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发表时间：
2016-09-07
影响因子：
4.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wang Z;Zhang H;Shi M;Yu Y;Wang H;Cao WM;Zhao Y;Zhang H
阿霉素（Dox，Adriamycin）已广泛用于乳腺癌的治疗。但其严重的心脏毒副作用限制了其临床应用。Dox治疗可诱导癌细胞DNA损伤及其他伴随效应，并随后激活核因子κB（NF-κB）通路，其在不同类型的恶性肿瘤中具有强烈的促生存作用。我们推测阻断NF-κB通路可能使乳腺癌细胞对Dox化疗敏感。TGFβ活化激酶1（TAK 1）是参与遗传毒性应激诱导的NF-κB活化的关键细胞内分子。靶向TAK 1作为增强癌症治疗疗效的策略已在几种恶性肿瘤中进行了研究。我们发现，NG 25，一种合成的TAK 1抑制剂，在一组乳腺癌细胞系中极大地增强了Dox治疗效果。在这项临床前研究中，我们发现NG 25部分阻断了Dox诱导的p38磷酸化和IκBα降解，并在所有测试的乳腺癌细胞系中增强了Dox诱导的细胞毒作用和凋亡。综上所述，我们提供了明确的证据表明，NG 25在体外使乳腺癌细胞对Dox治疗敏感。这种组合可能是一种有效和可行的治疗选择，最大限度地提高Dox疗效，同时最大限度地减少Dox治疗乳腺癌的副作用。
Doxorubicin (Dox, Adriamycin) has been widely used in breast cancer treatment. But its severe cardio-toxic side effects limited the clinical use. Dox treatment can induce DNA damage and other accompanying effects in cancer cells, and subsequently activates nuclear factor κB (NF-κB) pathway which has a strong pro-survival role in different types of malignancy. We hypothesize that blocking NF-κB pathway may sensitize breast cancer cells to Dox chemotherapy. TGFβ-activated kinase-1 (TAK1) is a key intracellular molecule participating in genotoxic stresses-induced NF-κB activation. Targeting TAK1 as a strategy to enhance cancer treatment efficacy has been studied in several malignancies. We showed that NG25, a synthesized TAK1 inhibitor, greatly enhanced Dox treatment efficacy in a panel of breast cancer cell lines. In this pre-clinical study, we found that NG25 partially blocked Dox-induced p38 phosphorylation and IκBα degradation and enhanced Dox-induced cytotoxic effects and apoptosis in all breast cancer cell lines tested. Taken together, we provided clear evidence that NG25 sensitizes the breast cancer cells to Dox treatment in vitro. This combination may be an effective and feasible therapeutic option maximizing Dox efficacy and meanwhile minimizing Dox side effects in treating breast cancer.
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影响因子：
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作者：
Figueroa-Magalhaes, Maria Cristina;Jelovac, Danijela;Connolly, Roisin M.;Wolff, Antonio C.
通讯作者：
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DOI：
10.6004/jnccn.2016.0037
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