Icariside II potentiates paclitaxel-induced apoptosis in human melanoma A375 cells by inhibiting TLR4 signaling pathway
Icariside II potentiates paclitaxel-induced apoptosis in human melanoma A375 cells by inhibiting TLR4 signaling pathway
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Icariside II 通过抑制 TLR4 信号通路增强紫杉醇诱导的人黑色素瘤 A375 细胞凋亡
DOI：
10.1016/j.fct.2012.06.027
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发表时间：
2012-09-01
影响因子：
4.3
通讯作者：
Xu, Jinhua
中科院分区：
文献类型：
--
作者：
Wu, Jinfeng;Guan, Ming;Xu, Jinhua
紫杉醇（taxol）与能够抑制生存信号的天然抗肿瘤药物联合治疗可能为新的化疗策略提供合理的分子基础。我们前期研究发现，淫羊藿中提取的icariside II （IS）通过调控细胞凋亡，在体内和体外抑制黑色素瘤细胞的增殖。在本报告中，我们研究了紫杉醇和IS在人黑色素瘤A375细胞中的联合作用。WST-8和PI检测显示，与紫杉醇单独治疗相比，IS和紫杉醇联合给药可增强细胞凋亡。同时，Western blot分析显示，IS和紫杉醇联合给药可导致末端促凋亡蛋白之一caspase-3的表达增加。在黑色素瘤中，IL-8和VEGF与疾病分期和高进展概率呈正相关。我们证明，与单独使用紫杉醇相比，IS联合紫杉醇治疗A375细胞可显著降低IL-8和VEGF的产生。最近的研究表明，TLR4-MyD88-ERK信号可能是逆转紫杉醇化疗耐药的新靶点。我们的流式细胞术和Western blot数据显示，紫杉醇激活了TLR4-MyD88-ERK信号，IS治疗可以有效抑制紫杉醇诱导的TLR4-MyD88-ERK信号的激活。总之，本研究首次证明IS可以增强紫杉醇诱导的黑色素瘤细胞凋亡。这些作用至少部分是通过抑制TLR4信号转导通路的激活来介导的。这些发现支持IS作为一种新的潜在抗肿瘤药物的进一步临床前评估。(C) 2012 Elsevier Ltd.版权所有。
Combination therapy of paclitaxel (taxol) with natural anti-tumor agents that are capable of inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Our previous study showed that icariside II (IS), derived from Herba Epimedii, inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. In this report, the combination effects of paclitaxel and IS were investigated in human melanoma A375 cells. As compared to the treatment with paclitaxel alone, the co-administration of IS and paclitaxel resulted in an enhancement of apoptosis as revealed by WST-8 and PI assays. Meanwhile, Western blot analysis showed that the co-administration of IS and paclitaxel resulted in increases of cleaved caspase-3, one of the terminal pro-apoptotic proteins. In melanoma, IL-8 and VEGF are positively correlated with disease stage and a high probability of progression. We demonstrated that treatment of A375 cells with IS in combination with paclitaxel resulted in a significant decrease in the production of IL-8 and VEGF, compared with paclitaxel alone. Recent studies suggest that TLR4-MyD88-ERK signaling may be a novel target for reversing chemoresistance to paclitaxel. Our flow cytometry and Western blot data showed that paclitaxel activated TLR4-MyD88-ERK signaling and that IS treatment could effectively inhibit this paclitaxel-induced activation of TLR4-MyD88-ERK signaling. In conclusion, this study demonstrated for the first time that IS could potentiate paclitaxel-induced apoptosis in melanoma cells. These effects were mediated, at least in part, by inhibiting the activation of the TLR4 signal transduction pathways. These findings support further preclinical evaluation of IS as a new potential anti-tumor agent. (C) 2012 Elsevier Ltd. All rights reserved.