TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor‐alpha in cancer cells
TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor‐alpha in cancer cells
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DOI：
10.1016/j.bcp.2016.10.014
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发表时间：
2017-01
影响因子：
5.8
通讯作者：
Pei-Yu Wang;Wenjun Zeng;Jie Liu;Yunlong Wu;Yingchao Ma;Zhiping Zeng;J. Pang;Xiao-kun Zhang
中科院分区：
文献类型：
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作者：
Pei-Yu Wang;Wenjun Zeng;Jie Liu;Yunlong Wu;Yingchao Ma;Zhiping Zeng;J. Pang;Xiao-kun Zhang
核维甲酸X受体-α（RXRα）主要通过其转录功能在细胞内环境稳定和许多生理过程中发挥重要作用。然而，RXRα的N端截短形式tRXRα在各种癌细胞和肿瘤组织中经常被描述，因此代表了一种新的有前途的药物靶点。我们最近发现雷公藤内酯醇（TR 01）可以靶向tRXRα的致癌活性。为了提高其肿瘤选择性，我们通过在C-14-羟基位点上引入不同的胺酯基团开发了几种TR 01衍生物。有趣的是，C-14修饰可以不同地影响tRXRα的表达，而不干扰其全长RXRα的水平。其中，TRC 4能显著降低tRXRα的表达，而TRC 5 -7则能显著增加tRXRα的表达，其抑制tRXRα表达的能力与其对AKT的失活和诱导多种肿瘤细胞凋亡密切相关。相反，用tRXRα稳定化合物TRC 5 -7处理癌细胞导致AKT活性和抗肿瘤能力增强。然而，尽管TR 01可强烈降低tRXRα表达和AKT活性，但它也强烈抑制正常细胞中RXRα的表达和转录活性。重要的是，不显著抑制RXRα转录功能的tRXRα选择性TRC 4保留了TR 01抗癌作用的最大效力，并且对正常细胞的活力没有显著影响。结论：tRXRα选择性TRC 4在药物靶点和副作用方面具有潜在的临床应用价值。我们的发现将为开发用于癌症治疗的改进的雷公藤内酯醇类似物提供新的策略。
The nuclear retinoid X receptor-α (RXRα) plays critical roles in cell homeostasis and in many physiological processes mainly through its transcriptional function. However, an N-terminal truncated form of RXRα, tRXRα, was frequently described in various cancer cells and tumor tissues, thus representing a new promising drug target. We recently demonstrated that triptolide (TR01) could target to the oncogenic activity of tRXRα. To improve its tumor selectivity, we developed several TR01 derivatives by introducing different amine ester groups on C-14-hydroxyl site. Interestingly, C-14 modification could differently affect the expression of tRXRα without interfering the level of its full length RXRα. Among the derivatives, TRC4 could strongly reduce tRXRα expression, while TRC5-7 increased it. The capability of inhibiting tRXRα expression was shown to be closely associated with its inactivation of AKT and induction of apoptosis in various cancer cells. Conversely, treatment of cancer cells with the tRXRα-stabilizing compounds TRC5-7 resulted in enhanced AKT activity and apoptosis-resistance. However, although TR01 could strongly reduce tRXRα expression and AKT activity, it also strongly inhibited the expression and transcriptional activity of RXRα in normal cells. Importantly, the tRXRα-selective TRC4 that did not significantly inhibit RXRα transcriptional function retained the most potency of the anticancer effect of TR01 and had no significant effect on the viability of normal cells. In conclusion, our results demonstrated that tRXRα-selective TRC4 will have potential clinical application in terms of drug target and side effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.