title: A novel andrographolide derivative AL-1 exerts its cytotoxicity on K562 cells through a ROS-dependent mechanism.
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.
authors.affiliation: Institute of Life and Health Engineering, and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, China.
authors.forename: Yong-Yang
authors.initials: YY
authors.lastname: Zhu
authors.forename: Guangchuang
authors.initials: G
authors.lastname: Yu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Wang
authors.forename: Guang-Rong
authors.initials: GR
authors.lastname: Yan
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D020543:Proteome / Q000032:analysis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004224:Diterpenes; D020543:Proteome; D017382:Reactive Oxygen Species; C030419:andrographolide; D008063:Thioctic Acid