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Front. Pharmacol. | doi: 10.3389/fphar.2019.01396

Antiproliferative and immunoregulatory effects of Azelaic acid against acute myeloid leukemia via activation of Notch signaling pathway

 Zhang Dongdong1, Yanxia Jin1, Tian Yang1, Qian Yang1,  Balu Wu1, Yanling Chen1, Ziyi Luo1, Li Liang1, Yujiao Liu1, Anjie Xu1, Xiqin Tong1, Can Can1, Lu Ding1, Honglei Tu1, Yuxin Tan1, Hongqiang Jiang1, Xiaoyan Liu2, Hui Shen2, Li Liu2,  Yunbao Pan2,  Yongchang Wei2 and  Zhou Fuling2*
  • 1Wuhan University, China
  • 2Zhongnan Hospital, Wuhan University, China

Acute myeloid leukemia (AML) had a poor prognosis and high incidence of relapse due to the therapeutic resistance. Azelaic acid (AZA) is a small molecular compound which exhibited antitumor effect. In this study, we report AZA can inhibit the proliferation of AML cells, laser confocal microscopy showed AZA-treated AML cells began to develop swelling and cytoplasmic vacuolization. Furthermore, AZA promotes the proliferation of NK and T cells and increases the secretion of TNF-α and IFN-γ, it also increases the expression levels of CD107a and TRAIL in NK cells and CD25 and CD69 in T cells to influence the activation and cytotoxic ability. AZA-treated NK cells can kill the AML cells more efficiently at the single-cell level observed under the micro-fluidic chips. Further mechanistic analysis using protein mass spectrometry analysis and Notch signaling reporter assay demonstrated that Notch1, Notch2 were up-regulated and the Notch signaling pathway was activated. Moreover, combination AZA with Notch inhibitor RO4929097 decreased the expression of Notch1, Notch2 and downstream HES1 and HEY1, made AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML. In vivo, AZA relieves the leukemic spleen infiltration and extends the survival, the percentage of CD3-CD56+ NK cells and CD4+CD8+ T cells as well as the secretion of cytotoxic cytokines are increased after the treatment of AZA. Our findings establish that AZA as a potential Notch agonist against AML by regulating the Notch signaling pathway.

Keywords: Azelaic acid, Acute Myeloid Leukemia, Notch signaling pathway, Notch agonist, immunoregulatory

Received: 25 Aug 2019; Accepted: 01 Nov 2019.

Copyright: © 2019 Dongdong, Jin, Yang, Yang, Wu, Chen, Luo, Liang, Liu, Xu, Tong, Can, Ding, Tu, Tan, Jiang, Liu, Shen, Liu, Pan, Wei and Fuling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Zhou Fuling, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei Province, China, zhoufuling@whu.edu.cn