title: 2',5'-Dihydroxychalcone-induced glutathione is mediated by oxidative stress and kinase signaling pathways.
abstract: Hydroxychalcones are naturally occurring compounds that continue to attract considerable interest because of their anti-inflammatory and antiangiogenic properties. They have been reported to inhibit the synthesis of the inducible nitric oxide synthase and to induce the expression of heme oxygenase-1. This study examines the mechanisms by which 2',5'-dihydroxychalcone (2',5'-DHC) induces an increase in cellular glutathione (GSH) levels using a cell line stably expressing a luciferase reporter gene driven by antioxidant-response elements (MCF-7/AREc32). The 2',5'-DHC-induced increase in cellular GSH levels was partially inhibited by the catalytic antioxidant MnTDE-1,3-IP(5+), suggesting that reactive oxygen species (ROS) mediate the antioxidant adaptive response. 2',5'-DHC treatment induced phosphorylation of the c-Jun N-terminal kinase (JNK) pathway, which was also inhibited by MnTDE-1,3-IP(5+). These findings suggest a ROS-dependent activation of the AP-1 transcriptional response. However, whereas 2',5'-DHC triggered the NF-E2-related factor 2 (Nrf2) transcriptional response, cotreatment with MnTDE-1,3-IP(5+) did not decrease 2',5'-DHC-induced Nrf2/ARE activity, showing that this pathway is not dependent on ROS. Moreover, pharmacological inhibitors of mitogen-activated protein kinase (MAPK) pathways showed a role for JNK and p38MAPK in mediating the 2',5'-DHC-induced Nrf2 response. These findings suggest that the 2',5'-DHC-induced increase in GSH levels results from a combination of ROS-dependent and ROS-independent pathways.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Remy
authors.initials: R
authors.lastname: Kachadourian
authors.forename: Subbiah
authors.initials: S
authors.lastname: Pugazhenthi
authors.forename: Kalpana
authors.initials: K
authors.lastname: Velmurugan
authors.forename: Donald S
authors.initials: DS
authors.lastname: Backos
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Franklin
authors.forename: Joe M
authors.initials: JM
authors.lastname: McCord
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002599:Chalcone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D008665:Metalloporphyrins; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D002599:Chalcone; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione