Inhibition of NF-κB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines
Inhibition of NF-κB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines
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DOI：
10.1016/j.leukres.2005.05.004
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发表时间：
2005-12-01
影响因子：
2.7
通讯作者：
Alvarez, E
中科院分区：
文献类型：
--
作者：
García, MG;Alaniz, L;Alvarez, E
多药耐药性（MDR）是癌症治疗失败的主要原因，其中涉及的机制之一是对细胞凋亡的抵抗。已在许多肿瘤中检测到组成型 NF-κ B 活性，有助于肿瘤发生和肿瘤存活，而抑制 NF-κ B 活性已被证明可增强化疗药物诱导的细胞死亡。因此，使用 BAY 11-7082（一种 Iκ B-α 磷酸化的不可逆抑制剂）可能有益于某些肿瘤的治疗。尽管有几份报告证明细胞毒性药物可短暂激活 NF-κ B，但人们对 NF-κ B 激活在白血病细胞化疗耐药表型发展中的作用知之甚少。在本研究中，我们分析了 NF-kappa B 与小鼠白血病耐药细胞系存活的关系。评估了 BAY 11-7082 以及化疗药物长春新碱和阿霉素对该转录因子的调节作用。还研究了 BAY 11-7082 对含有 NF-κ B 结合位点的基因表达的影响。我们发现细胞系 LBR-V160 和 LBR-D160（分别对长春新碱和阿霉素耐药）比敏感的 LBR- 表现出更高的 NF-κ B 组成型活性，并且活性复合物包含 p50 和 p65 亚基。 BAY 11-7082 (3.5 μM) 抑制三种细胞系中的组成型 NF-κ B 活性，而抗癌剂则不然。 BAY 11-7082 处理在 LBR-V160 和 LBR-D160 中诱导的细胞凋亡百分比高于 LBR-。用 BAY 11-7082 处理的细胞表现出对 NF-κ B 诱导基因（例如 IL-10 IL-15 TNF-α 和 TGF-β）的调节。一起拍摄。这些数据表明，BAY 11-7082 对组成型 NF-κ B 活性的抑制可能是治疗 MDR 白血病的有效方法。 (C) 2005 Elsevier Ltd. 保留所有权利。
Multidrug resistance (MDR) is the main reason for failure of cancer therapy with resistance to apoptosis being one of the mechanisms involved. Constitutive NF-kappa B activity has been detected in many tumors contributing to oncogenesis and tumor survival whereas inhibition of NF-kappa B activity has proved to enhance cell death induced by chemotherapeutic agents. Consequently, the use of BAY 11-7082, an irreversible inhibitor of I kappa B-alpha phosphorylation, could be beneficial in the treatment of certain tumors. Although there are several reports which demonstrate a transient activation of NF-kappa B by cytotoxic drugs, little is known about the role of NF-kappa B activation in the development of a chemoresistant phenotype in leukemic cells. In this Study, we analyzed the relationship between NF-kappa B and the survival of murine leukemic drug resistant cell lines. The modulation of this transcription factor by BAY 11-7082 and the chemotherapeutic agents vincristine and doxorubicin was evaluated. The effect of BAY 11-7082 on the expression of genes containing NF-kappa B-binding sites was also studied. We found that the cell lines LBR-V160 and LBR-D160 (resistant to vincristine and doxorubicin, respectively) presented higher constitutive NF-kappa B activity than the sensitive LBR- and the active complex contained both p50 and p65 subunits. BAY 11-7082 (3.5 mu M) inhibited constitutive NF-kappa B activity in the three cell lines whereas the anticancer agents did not. Treatment with BAY 11-7082 induced a higher percentage of apoptosis in LBR-V160 and LBR-D160 than in LBR-. Cells treated with BAY 11-7082 displayed modulation of NF-kappa B-inducible genes such as IL-10 IL-15 TNF-alpha and TGF-beta. Taken together. these data suggest that suppression of constitutive NF-kappa B activity by BAY 11-7082 may be a useful treatment for MDR leukemias. (C) 2005 Elsevier Ltd. All rights reserved.