BMS-345541 targets inhibitor of κB kinase and induces apoptosis in melanoma:: Involvement of nuclear factor κB and mitochondria pathways
BMS-345541 targets inhibitor of κB kinase and induces apoptosis in melanoma:: Involvement of nuclear factor κB and mitochondria pathways
复制标题
DOI：
10.1158/1078-0432.ccr-05-1220
复制
发表时间：
2006-02-01
影响因子：
11.5
通讯作者：
Richmond, A
中科院分区：
文献类型：
--
作者：
Yang, JM;Amiri, KI;Richmond, A
目的：黑色素瘤中κ B激酶抑制剂（IKK）的组成性激活可使黑色素瘤对细胞凋亡和化疗产生抵抗。IKK是否能够作为黑色素瘤的治疗靶点尚不清楚。我们通过使用BMS-345541（一种具有高度选择性IKK抑制活性的新型化合物）来触发黑色素瘤细胞凋亡，探索了将IKK作为黑色素瘤治疗靶点的可能性。三种人黑素瘤细胞系（SK-MEL-5，Hs 294 T和A375），它们都具有高组成型IKK活性，作为BMS-345541治疗的体外和体内黑色素瘤模型。使用两种已知抗肿瘤药物（替莫唑胺和硼替佐米）作为平行对照，评价BMS-345541的疗效和毒性。BMS-345541对核因子-κ B（NF-κ B）信号传导和凋亡机制的影响进行了研究。结果：BMS-345541抑制组成型IKK活性导致体外和体内培养的黑素瘤细胞NF-κ B活性、CXCL 1趋化因子分泌和黑素瘤细胞存活减少。BMS-345541对肿瘤细胞生长的影响是通过细胞凋亡介导的细胞凋亡，基于凋亡诱导因子的释放、线粒体膜电位的耗散和线粒体中B细胞淋巴瘤基因-2（Bcl-2）/Bcl相关X蛋白（Bax）的比率降低。结论：BMS-345541下调IKK活性可导致黑色素瘤细胞凋亡，这是因为黑色素瘤细胞的程序性细胞死亡机制受到NF-κ B B信号的高度调节。因此，IKK可能作为黑色素瘤治疗的潜在靶点。
Purpose: Constitutive activation of inhibitor of kappa B kinase (IKK) confers melanoma resistance to apoptosis and chemotherapy. Whether IKK is able to serve as a therapeutic target in melanoma is unknown. We explored the possibility of exploiting IKK as a therapeutic target in melanoma by using BMS-345541, a novel compound with a highly selective IKK inhibitory activity, to trigger melanoma cell apoptosis.Experimental Design: Three human melanoma cell lines (SK-MEL-5, Hs 294T and A375), all of which have high constitutive IKK activities, served as in vitro and in vivo melanoma models for treatment with BMS-345541. Two known antitumor drugs (temozolomide and bortezomib) were used as parallel controls for evaluation of the therapeutic efficiency and toxicity of BMS-345541. The effects of BMS-345541 on nuclear factor kappa B (NF-kappa B) signaling and on the apoptosis machinery were investigated.Results: Inhibition of constitutive IKK activity by BMS-345541 resulted in the reduction of NF-kappa B activity, CXCL1 chemokine secretion by cultured melanoma cells and melanoma cell survival in vitro and in vivo. The effect of BMS-345541 on tumor cell growth was through mitochondria-mediated apoptosis, based on the release of apoptosis-inducing factor, dissipation of mitochondrial membrane potential, and reduced ratio of B cell lymphoma gene-2 (Bcl-2)/Bcl-associated X protein (Bax) in mitochondria. The BMS-345541 execution of apoptosis was apoptosis-inducing factor-dependent, but largely caspase-independent.Conclusion: BMS-345541 down-regulation of IKK activity results in mitochondria-mediated apoptosis of tumor cells because the programmed cell death machinery in melanoma cells is highly regulated by NF-kappa B signaling. Therefore, IKK may serve as a potential target for melanoma therapy.