title: Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation.
abstract: Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS). Considering that ROS generation depends on electrophilicity of PL, PL-CL was designed as its analog by introducing the α-substituent chlorine on the lactam ring to increase moderately its electrophilicity. In comparison with the parent molecule, this molecule was identified as a stronger ROS (O2(∙-) and H2O2) inducer and cytotoxic agent, and manifested more than 15-fold selectivity toward A549 cells over normal WI-38 cells. Mechanistic study uncovers for the first time that the selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation. Stronger intracellular TrxR inhibition and higher accumulation of ROS (O2(∙-) and H2O2) are responsible for more effective S-phase arrest and mitochondria-mediated apoptotic induction of A549 cells by PL-CL than PLvia p53-p21-cyclinA/CDK2 and ASK1-JNK/p38 signaling cascade pathways, respectively. This work provides an example of successfully designing PL-directed anticancer agent by an electrophilicity-based prooxidant (ROS-generating agent) strategy and gives added confidence for extending this strategy to other natural products.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Cui-Hong
authors.initials: CH
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: bozhou@lzu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics*; D010881:Piperidones
chemical_list: D004148:Dioxolanes; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase; C482858:MAP3K5 protein, human; C498077:piperlongumine; D010881:Piperidones
keywords: Electrophilicity; Piperlongumine; Prooxidant; Reactive oxygen species; Thioredoxin reductase