A novel andrographolide derivative AL-1 exerts its cytotoxicity on K562 cells through a ROS-dependent mechanism

Authors

  • Yong-Yang Zhu,

    1. Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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    • These authors contributed equally to this work.

  • Guangchuang Yu,

    1. Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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    • These authors contributed equally to this work.

  • Ye Zhang,

    1. Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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  • Zheng Xu,

    1. Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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  • Yu-Qiang Wang,

    1. Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China
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  • Guang-Rong Yan,

    Corresponding author
    • Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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  • Qing-Yu He

    1. Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China
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  • Colour Online: See the article online to view Figs. 1, 3, and 4 in colour.

Correspondence: Dr. Guang-Rong Yan, Institute of Life and Health Engineering, and National Engineering and Research Center for Genetic Medicine, Jinan University, Guangzhou 510632, China

E-mail: tgryan@jnu.edu.cn

Fax: +86-20-85227039

Abstract

Andrographolide-lipoic acid conjugate (AL-1) is a new in-house synthesized chemical entity, which was derived by covalently linking andrographolide with lipoic acid. However, its anti-cancer effect and cytotoxic mechanism remains unknown. In this study, we found that AL-1 could significantly inhibit cell viability of human leukemia K562 cells by inducing G2/M arrest and apoptosis in a dose-dependent manner. Thirty-one AL-1-regulated protein alterations were identified by proteomics analysis. Gene ontology and ingenuity pathway analysis revealed that a cluster of proteins of oxidative redox state and apoptotic cell death-related proteins, such as PRDX2, PRDX3, PRDX6, TXNRD1, and GLRX3, were regulated by AL-1. Functional studies confirmed that AL-1 induced apoptosis of K562 cells through a ROS-dependent mechanism, and anti-oxidant, N-acetyl-l-cysteine, could completely block AL-1-induced cytotoxicity, implicating that ROS generation played a vital role in AL-1 cytotoxicity. Accumulated ROS resulted in oxidative DNA damage and subsequent G2/M arrest and mitochondrial-mediated apoptosis. The current work reveals that a novel andrographolide derivative AL-1 exerts its anticancer cytotoxicity through a ROS-dependent DNA damage and mitochondrial-mediated apoptosis mechanism.

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