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

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.

Secondary Metabolites Produced by Macrophomina phaseolina Isolated from Eucalyptus globulus

“…Azelaic acid has antimicrobial and anti-inflammatory properties finding application in the treatment of skin diseases. Furthermore, its activity against several tumor cells has also been documented [41].…”

Structural and In Silico Characterization of Small Molecules Isolated from Eichhornia crassipes

“…Its derivatives such as hydroquinone 5-O-cinnamoyl ester and some alkyl and prenylated derivatives have also been reported to have cytotoxic activities against lung cancer [20][21][22], meaning that more optimization of the compound has a potential to develop more drug lead options against cancers. Nonanedioic acid (2) has antitumor properties in humans [23], antineoplastic and antileukemic activities [24], immunoregulatory and antiproliferative activities against cancer cells [25,26], and cytotoxic activities and anti-inflammatory and antioxidant activities [27]. Some of its derivatives have also shown to be active against cancers [26] which give a good promise of its usefulness in drug development against cancers and other diseases.…”

Azelaic Acid Exerts Antileukemia Effects against Acute Myeloid Leukemia by Regulating the Prdxs/ROS Signaling Pathway

“…In addition, Notch is an important regulator of immune cell development and function [ 58 ]. Our previous study had identified that AZA could activate the Notch signaling pathway and enhance the cytotoxicity of immune effector cells against AML [ 59 ]. However, whether AZA can alleviate immunosuppression in the tumor microenvironment via the regulation of Prdxs and Notch requires further study.…”