1. TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity
- Author
-
Dongqing Guo, Weili Li, Xiaoqian Sun, Qian Zhang, Yanyan Jiang, Chun Li, Yong Wang, Qiyan Wang, Xiaoping Wang, and Wenji Lu
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Dihydrotanshinone I ,TFEB-NF-κB ,Apoptosis ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Humans ,Doxorubicin ,Myocytes, Cardiac ,Phosphorylation ,Furans ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Zebrafish ,Cell Proliferation ,Inflammation ,Cardiotoxicity ,Antibiotics, Antineoplastic ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Macrophages ,Research ,NF-kappa B ,Quinones ,NF-κB ,Phenanthrenes ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Cancer research ,TFEB ,Cytokines ,Signal transduction ,medicine.drug - Abstract
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-κB 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 IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB. 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-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.
- Published
- 2020