Identification of H2S/NO-donating artemisinin derivatives as potential antileukemic agents

Xuemei Chen; Pei Huang; Jing Wang; Runmei Tian; Yan Chen; Yongzheng Chen; Lei Zhang; Zhigui Ma

doi:10.1039/C9RA08239E

Identification of H₂S/NO-donating artemisinin derivatives as potential antileukemic agents†

Xuemei Chen,^a Pei Huang,

^b Jing Wang,

^cd Runmei Tian,^b Yan Chen,*^b Yongzheng Chen,

^cd Lei Zhang

*^cd and Zhigui Ma*^a

Author affiliations

* Corresponding authors

^a Department of Pediatric Hematology, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China
E-mail: zhiguima@scu.edu.cn

^b Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, PR China
E-mail: cyz600@163.com

^c Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China
E-mail: lzhang@zmu.edu.cn

^d Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563003, PR China

Abstract

Three H₂S/NO-donating artemisinin derivatives were designed and synthesized. Their antiproliferative activities were evaluated against human acute myeloid leukemia (AML) cell lines of K562 and K562/ADR and human normal liver cells of LO2. Biological evaluation indicated that NO-donating compound 10c exhibited the most potent cytotoxicity against leukemia cells, similar to the bioactivity of clinical drug of homoharringtonine, but showed less toxicity than homoharringtonine against LO2 cells. Further mechanism studies revealed that 10c could enhance the levels of intracellular NO and ROS, induce apoptosis and S phase cell cycle arrest, and disturb the mitochondrial membrane potential in K562 and K562/ADR cells. Western blot results demonstrated that 10c noticeably promoted autophagy by up-regulating the levels of Beclin1 and L3-II expression, inhibited the AKT signaling, and stimulated the AMPK and JNK signaling in both leukemia cell lines. Overall, 10c exhibited the potential to be a promising candidate for the therapy of AML.

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Article information

DOI: https://doi.org/10.1039/C9RA08239E
Article type: Paper
Submitted: 10 Oct 2019
Accepted: 16 Dec 2019
First published: 02 Jan 2020
This article is Open Access

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RSC Adv., 2020,10, 501-511

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Identification of H₂S/NO-donating artemisinin derivatives as potential antileukemic agents

X. Chen, P. Huang, J. Wang, R. Tian, Y. Chen, Y. Chen, L. Zhang and Z. Ma, RSC Adv., 2020, 10, 501 DOI: 10.1039/C9RA08239E

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