Inhibition of Constitutive Activity of Nuclear Transcription Factor kappaB Sensitizes Doxorubicin-Resistant Cells to Apoptosis (Retracted article. See vol. 114, pg. 1456, 2013)
Inhibition of Constitutive Activity of Nuclear Transcription Factor kappaB Sensitizes Doxorubicin-Resistant Cells to Apoptosis (Retracted article. See vol. 114, pg. 1456, 2013)
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DOI：
10.1002/jcb.22115
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发表时间：
2009-05-15
影响因子：
4
通讯作者：
Manna, Sunil K.
中科院分区：
文献类型：
--
作者：
Gangadharan, Charitha;Thoh, Maikho;Manna, Sunil K.
阿霉素是治疗各种肿瘤最有效的药物之一。其使用受到细胞凋亡抗性的限制，其机制尚不完全清楚。核转录因子 kappaB (NF-kappa B) 已被证明可以阻止细胞凋亡并促进细胞增殖，因此被认为是抗癌药物开发的重要靶点。我们发现，在野生型和 Dox 回复型 MCF-7 细胞中，阿霉素诱导的 NF-κ B 是短暂的，而 Dox 抗性细胞表现出 NF-κ B 的高基础活性和依赖于它的基因表达。此外，通过活性氧中间体生成、脂质过氧化、细胞毒性、PARP 降解和 Bcl-2 表达测定检测发现，在耐药细胞中，阿霉素不能诱导细胞凋亡。在 Dox 耐药细胞中发现了多药耐药蛋白和转谷氨酰胺酶的高基础表达，抑制 NF-κ B 会降低这些表达量，并且还会使这些细胞对阿霉素敏感。这些观察结果共同表明，高 NF-κ B 活性赋予对阿霉素的抗性，并且其抑制作用会增强细胞凋亡。这项研究表明 NF-κ B 在化疗耐药中发挥着重要作用，并证实了抑制 NF-κ B 将成为化疗新方法的事实。 J.细胞。生物化学。 107: 203-213, 2009。(C) 2009 Wiley-Liss, Inc.
Doxorubicin is one of the most effective agents used in the treatment of various tumors. Its use is restricted by the development of resistance to apoptosis, the mechanism of which is not fully understood. Nuclear transcription factor kappaB (NF-kappa B) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered as an important target for anticancer drug development. We found that in wild type and Dox-revertant MCF-7 cells, Doxorubicin induced NF-kappa B was transient and Dox-resistant cells showed high basal activity of NF-kappa B and expression of genes dependent on it. Moreover, in resistant cells Doxorubicin was unable to induce apoptosis as detected by assays for reactive oxygen intermediates generation, lipid peroxidation, cytotoxicity, PARP degradation and Bcl-2 expression. High basal expressions of multi-drug resistant protein and transglutaminase were found in Dox-resistant cells and inhibition of NF-kappa B decreased those amounts and also sensitized these cells by Doxorubicin. These observations collectively suggest that high NF-kappa B activity confers resistance to Doxorubicin and its inhibition potentiates apoptosis. This study indicates that NF-kappa B plays an important role in chemoresistance and establishes the fact that inhibition of NF-kappa B will be a novel approach in chemotherapy. J. Cell. Biochem. 107: 203-213, 2009. (C) 2009 Wiley-Liss, Inc.