Celastrol inhibits proliferation and induces chemosensitization through down-regulation of NF-κB and STAT3 regulated gene products in multiple myeloma cells
Celastrol inhibits proliferation and induces chemosensitization through down-regulation of NF-κB and STAT3 regulated gene products in multiple myeloma cells
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DOI：
10.1111/j.1476-5381.2011.01449.x
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发表时间：
2011-11-01
影响因子：
7.3
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
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作者：
Kannaiyan, Radhamani;Hay, Hui Sin;Sethi, Gautam
背景与目的促炎转录因子核因子-kappaB和信号转导与转录激活子3(STAT3)的激活是多发性骨髓瘤(MM)发病和化疗耐药的重要因素之一，导致高死亡率。因此，在本研究中，我们研究了雷公藤红素是否可以通过干扰核因子-kappaB和STAT3激活途径来抑制MM细胞的增殖和诱导化疗增敏。实验方法利用虚拟预测肿瘤细胞系统和对阿霉素、马法兰和硼替佐米耐药的不同MM细胞系来研究雷公藤红素的作用。它还能协同增强沙利度胺和硼替佐米的促凋亡作用。这与多种增殖和抗凋亡基因产物的下调有关，这些基因产物包括细胞周期蛋白d1、bcl2、bclxl、Survivin、XIAP和Mcl-1。雷公藤红素的这些作用是通过抑制I-kappa Bα激酶的激活和I-kappa Bα和p65的磷酸化而抑制结构性活性的核因子-kappaB。雷公藤红素还抑制STAT3的结构性激活和IL6诱导的STAT3的激活，诱导细胞凋亡，表现为亚G1期细胞积聚增加，促凋亡蛋白表达增加，caspase-3激活。结论：根据我们的实验结果，雷公藤红素可能对MM和其他血液系统恶性肿瘤有很大的治疗潜力。
BACKGROUND AND PURPOSEActivation of pro-inflammatory transcription factors NF-kappa B and signal transducer and activator of transcription 3 (STAT3) is one of the major contributors to both pathogenesis and chemoresistance in multiple myeloma (MM), which results in high mortality rate. Thus, in the present study, we investigated whether celastrol could suppress the proliferation and induce chemosensitization of MM cells by interfering with NF-kappa B and STAT3 activation pathways.EXPERIMENTAL APPROACHThe effects of celastrol were investigated using both a virtual predictive tumour cell system and different MM cell lines resistant to doxorubicin, melphalan and bortezomib.KEY RESULTSCelastrol inhibited the proliferation of MM cell lines regardless of whether they were sensitive or resistant to bortezomib and other conventional chemotherapeutic drugs. It also synergistically enhanced the apoptotic effects of thalidomide and bortezomib. This correlated with the down-regulation of various proliferative and anti-apoptotic gene products including cyclin D1, Bcl-2, Bcl-xL, survivin, XIAP and Mcl-1. These effects of celastrol were mediated through suppression of constitutively active NF-kappa B induced by inhibition of I kappa B alpha kinase activation; and the phosphorylation of I kappa B alpha and of p65. Celastrol also inhibited both the constitutive and IL6-induced activation of STAT3, which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase, an increase in the expression of pro-apoptotic proteins and activation of caspase-3.CONCLUSIONS AND IMPLICATIONSThus, based on our experimental findings, we conclude that celastrol may have great potential as a treatment for MM and other haematological malignancies.