Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production
Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production
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DOI：
10.1007/s10549-012-2196-0
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发表时间：
2012-10-01
影响因子：
3.8
通讯作者：
Huang, Ruo-Pan
中科院分区：
文献类型：
--
作者：
Shi, Zhi;Yang, Wei-Min;Huang, Ruo-Pan
抗药性仍然是癌症治疗成功的主要障碍。多药耐药(MDR)的发生与多药耐药相关蛋白的过度表达、药物代谢增加、细胞凋亡减少、信号转导通路受损等多种机制有关。最近的研究有力地表明，细胞因子与耐药性之间存在密切联系。为了寻找新的耐药靶点，我们建立了耐多药的人乳腺癌细胞系MCF-7/R，并利用细胞因子抗体阵列技术检测了细胞因子的表达谱。在筛选的120种细胞因子/趋化因子中，IL-6、IL-8等13种蛋白在耐药细胞株中较敏感细胞株显著升高，而在耐药细胞株中有7种蛋白特异性降低。抗IL-6和IL-8的中和抗体部分逆转了MCF-7/R对紫杉醇和阿霉素的耐药性，而抗MCP-1的中和抗体无明显作用。应用siRNA技术抑制内源性IL-6或IL-8可显著提高MCF-7/R细胞的药物敏感性。此外，IL-6或IL-8的过表达增加了MCF-7/S细胞对阿霉素的耐药性。我们的数据表明，IL-6和IL-8表达水平的增加可能与人乳腺癌细胞的多药耐药有关。
Drug resistance remains a major hurdle to successful cancer treatment. Many mechanisms such as overexpression of multidrug-resistance related proteins, increased drug metabolism, decreased apoptosis, and impairment of signal transduction pathway can contribute multidrug resistance (MDR). Recent studies strongly suggest a close link between cytokines and drug resistance. To identify new targets involved in drug resistance, we established a multidrug-resistant human breast cancer cell line MCF-7/R and examined the cytokine profile using cytokine antibody array technology. Among 120 cytokines/chemokines screened, IL-6, IL-8, and 13 other proteins were found to be markedly increased in drug-resistant MCF-7/R cell line as compared to sensitive MCF-7/S cell line, while 7 proteins were specifically reduced in drug-resistant MCF-7/R cells. Neutralizing antibodies against IL-6 and IL-8 partially reversed the drug resistance of MCF-7/R to paclitaxel and doxorubicin, while a neutralizing antibody against MCP-1 had no significant effect. Inhibition of endogenous IL-6 or IL-8 by siRNA technology significantly enhanced drug sensitivity of MCF-7/R cells. Furthermore, overexpression of IL-6 or IL-8 expression by transfection increased the ADM resistance in MCF-7/S cells. Our data suggest that increased expression levels of IL-6 and IL-8 may contribute to MDR in human breast cancer cells.