TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity
TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity
复制标题
TFEB-NF-kappa B 炎症信号轴：二氢丹参酮 I 在阿霉素诱导的心脏毒性中的新治疗途径
DOI：
10.1186/s13046-020-01595-x
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发表时间：
2020-05-24
影响因子：
11.3
通讯作者：
Wang, Yong
中科院分区：
文献类型：
--
作者：
Wang, Xiaoping;Wang, Qiyan;Wang, Yong
多柔比星对多种实体瘤和血液系统恶性肿瘤有效。不幸的是，由于累积的剂量依赖性心脏毒性，阿霉素的临床应用受到限制。二氢丹参酮I（Dihydrotanshinone I，DHT）是丹参（Salvia miltiorrhiza Bunge）的天然产物，具有多种抗肿瘤和抗炎作用。然而，其抗阿霉素诱导的心脏毒性（DIC）的作用，无论是在体内还是在体外，尚未阐明。本研究旨在探讨二氢睾酮对DIC的抗炎作用，并探讨其可能的调控机制。方法采用斑马鱼、C57 BL/6小鼠和H9 C2心肌细胞观察DHT对DIC的影响。采用超声心动图、组织学检查、流式细胞术、免疫组化和免疫荧光等方法评价其心肌保护作用和抗炎作用。应用mTOR激动剂和携带GFP-TFEB的慢病毒载体来探索调控信号通路。结果在体内外，二氢睾酮通过抑制M1巨噬细胞的活化和促炎细胞因子的过度释放而改善心功能。DHT抑制了NF-kappa B的激活和核定位，mTOR激动剂消除了该作用，同时减少了核TFE B的表达。此外，细胞核TFE B表达减少伴随着IKK α/β和NF-κ B B磷酸化上调，而TFE B过表达逆转了这些变化。有趣的是，DHT可上调TFE B的核表达，并降低p-IKK α/β和p-NF-κ B的表达。结论二氢睾酮可能通过mTOR-TFE B-NF-κ B B信号通路发挥抗炎作用。当前的研究表明TFEB-IKK-NF-κ B信号轴是一种以前未描述的DIC药物途径。
Background Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. Methods Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. Results DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-kappa B were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKK alpha/beta and NF-kappa B, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKK alpha/beta and p-NF-kappa B. Conclusions Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-kappa B signaling pathway. The current study implicates TFEB-IKK-NF-kappa B signaling axis as a previously undescribed, druggable pathway for DIC.