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

Dongdong Zhang,Yongchang Wei,Ziyi Luo,Qian Yang,Fuling Zhou,Yanxia Jin,Yanling Chen,Balu Wu,Yufeng Shang,Xiaoyan Liu,Tian Yang,Luciano Saso

doi:10.1155/2020/1295984

Dongdong Zhang, Yongchang Wei + Show 10 more

Open Access

https://doi.org/10.1155/2020/1295984

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Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with a poor prognosis attributed to elevated reactive oxygen species (ROS) levels. Thus, agents that inhibit ROS generation in AML should be exploited. Azelaic acid (AZA), a small molecular compound, can scavenge ROS and other free radicals, exerting antitumor effects on various tumor cells. Herein, this study evaluated the antileukemic activity of AZA against AML via regulation of the ROS signaling pathway. We found that AZA reduced intracellular ROS levels and increased total antioxidant capacity in AML cell lines and AML patient cells. AZA suppressed the proliferation of AML cell lines and AML patient cells, expending minimal cytotoxicity on healthy cells. Laser confocal microscopy showed that AZA-treated AML cells surged and ruptured gradually on microfluidic chips. Additionally, AZA promoted AML cell apoptosis and arrested the cell cycle at the G1 phase. Further analysis demonstrated that peroxiredoxin (Prdx) 2 and Prdx3 were upregulated in AZA-treated AML cells. In vivo, AZA prolonged survival and attenuated AML by decreasing CD33+ immunophenotyping in the bone marrow of a patient-derived xenograft AML model. Furthermore, mice in the AZA-treated group had an increased antioxidant capacity and Prdx2/Prdx3 upregulation. The findings indicate that AZA may be a potential agent against AML by regulating the Prdxs/ROS signaling pathway.

Highlights

Acute myeloid leukemia (AML) is one of the most common hematological malignancies with a rapidly progressive and poor prognosis
Increased Reactive oxygen species (ROS) levels have been correlated with phenotypic change in hematopoietic stem cells (HSCs) and loss of HSC quiescence, and excessive oxygen limits the lifespan of HSCs by regulating the ROS-p38 MAPK pathway [12]
The collected cells were stained with dichlorodihydrofluorescein diacetate (DCF-DA), and ROS levels were analyzed by flow cytometry. (b) Statistical analysis of the intracellular ROS levels after AML cell lines and AML patient cells were treated with 5 mM Azelaic acid (AZA) for 24 h. (c–f) U937, HL60, and Molm-13 cells were treated with 5.0 mM AZA for 24 h

Summary

Introduction

Acute myeloid leukemia (AML) is one of the most common hematological malignancies with a rapidly progressive and poor prognosis. Low ROS levels are required to initiate and promote tumor growth; moderate ROS levels are involved in the inflammatory response, while high ROS levels contribute to apoptosis and autophagy [13] Both ROS-elevating and ROS-eliminating strategies have been developed to treat cancer [14]. AML patients with FMS-like tyrosine kinase 3 (FLT3) mutations have high relapse rates because FLT3 induces elevated ROS levels [20, 21]. AZA exhibits antitumor effects on several tumor cells, such as lentigo maligna [30], malignant melanoma [31], lymphoma [32], and human T lymphotropic virus 1- (HLTV-1-) infected T-cell leukemia [33], by inhibiting Trx reductase activity, ROS generation, and DNA synthesis in tumor cells [28, 31, 33]. In the present study, we examined the antileukemia activity of AZA and further explored its molecular basis

Materials and Methods

Results

Discussion

D21 Sacrifice

Conflicts of Interest