Antiproliferative and Immunoregulatory Effects of Azelaic Acid Against Acute Myeloid Leukemia via the Activation of Notch Signaling Pathway.

Zhang Dongdong,Yanling Chen,Li Liang,Can Can,Hui Shen,Yunjiao Liu,Honglei Tu,Hongqiang Jiang,Yongchang Wei,Anjie Xu,Balu Wu,Li Liu,Yunbao Pan,Fuling Zhou,Xiqin Tong,Tian Yang,Qian Yang,Xiaoyan Liu,Liang Ding ,Yifei Jin ,Yurong Tan ,志偉 羅

doi:10.3389/fphar.2019.01396

Zhang Dongdong, Yanling Chen + Show 20 more

Open Access

https://doi.org/10.3389/fphar.2019.01396

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Abstract

Acute myeloid leukemia (AML) is a common type of hematological malignancy that can progress rapidly. AML has a poor prognosis and a high incidence of relapse due to therapeutic resistance. Azelaic acid (AZA), a small molecular compound is known to exhibit antitumor effect on various tumor cells. This study aimed to evaluate the antiproliferative and immunoregulatory effects of AZA against AMLviathe activation of the notch signaling pathway. We found that AZA can inhibit the proliferation of AML cells. In addition, laser confocal microscopy showed AZA-treated AML cells began to swelling and undergo cytoplasmic vacuolization. Importantly, AZA promoted the proliferation of NK and T cells and increased the secretion of TNF-αand IFN-γ. AZA also increased the expression levels of CD107a and TRAIL in NK cells, and CD25 and CD69 in T cells to influence their activation and cytotoxic ability. AZA-treated NK cells can kill AML cells more efficiently at the single-cell level as observed under the microfluidic chips. Further mechanistic analysis using protein mass spectrometry analysis and Notch signaling reporter assay demonstrated that Notch1and Notch2 were up-regulated and the Notch signaling pathway was activated. Moreover, combining AZA with the Notch inhibitor, RO4929097, decreased the expression of Notch1and Notch2, and downstream HES1 and HEY1, which rendered AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML. In vivo, AZA relieved the leukemic spleen infiltration and extended the survival. The percentage of CD3-CD56+NK cells and CD4+CD8+T cells as well as the secretion of cytotoxic cytokines was increased after the treatment of AZA. The overall findings reveal that AZA is a potential Notch agonist against AML in activating the Notch signaling pathway.

Highlights

Acute myeloid leukemia (AML) is a hematological malignancy arising from hematopoietic stem cells
A previous study demonstrated that Azelaic acid (AZA) can inhibit the proliferation of AML cells at low micromolar level (Pan et al, 2017) and our experimental results further verified this conclusion
We did not observe any obvious apoptosis in healthy PBMC at the same AZA concentration (Figure 1C), suggesting that AZA can selectively inhibit the proliferation of AML cells

Summary

Introduction

Acute myeloid leukemia (AML) is a hematological malignancy arising from hematopoietic stem cells. AML is a common form of acute leukemia in adults with poor prognosis. 25% of patients survival 5 years after their diagnosis (Beyar-Katz and Gill, 2018) and AML treatment remains largely unchanged over the past several decades. High dose chemotherapy for inhibiting the accumulation of leukemic blasts, consolidation chemotherapy, and a stem cell transplant during remission remain as the main methods of AML treatment. The remission method is difficult to maintain without subsequent treatment and the toxic side effects of chemotherapy, such as the myelosuppression or subsequent severe infection, render some patients intolerable to treatment. Some novel targeted therapies and chemotherapeutic agents benefit more AML patients, overall survival remains low due to drug resistance and disease recurrence (Yanada and Naoe, 2012)

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