title: Hexamethoxylated Monocarbonyl Analogues of Curcumin Cause G2/M Cell Cycle Arrest in NCI-H460 Cells via Michael Acceptor-Dependent Redox Intervention.
abstract: Curcumin, derived from the dietary spice turmeric, holds promise for cancer prevention. This prompts much interest in investigating the action mechanisms of curcumin and its analogues. Two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogues were reported to possess significantly enhanced cytotoxicity compared with the parent molecule. However, the detailed mechanisms remain unclear. In this study, compounds 1 and 2 were identified as the G2/M cell cycle arrest agents to mediate the cytotoxicity toward NCI-H460 cells via Michael acceptor-dependent redox intervention. Compared with curcumin, they could more easily induce a burst of reactive oxygen species (ROS) and collapse of the redox buffering system. One possible reason is that they could more effectively target intracellular TrxR to convert this antioxidant enzyme into a ROS promoter. Additionally, they caused up-regulation of p53 and p21 and down-regulation of redox-sensitive Cdc25C along with cyclin B1/Cdk1 in a Michael acceptor- and ROS-dependent fashion. Interestingly, in comparison with compound 2, compound 1 displayed a relatively weak ability to generate ROS but increased cell cycle arrest activity and cytotoxicity probably due to its Michael acceptor-dependent microtubule-destabilizing effect and greater GST-inhibitory activity, as well as its enhanced cellular uptake. This work provides useful information for understanding Michael acceptor-dependent and redox-mediated cytotoxic mechanisms of curcumin and its active analogues.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China.|Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Institute of Applied Chemistry, Shaoxing University , Shaoxing, Zhejiang 312000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gansu Provincial Hosipital , Lanzhou, Gansu 730000, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University , 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 , Lanzhou, Gansu 730000, China.
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China.
authors.forename: Zhi-Shan
authors.initials: ZS
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003474:Curcumin
keywords: cell cycle; curcumin; reactive oxygen species; redox modulation; thioredoxin reductase