title: Enhancement of the Effect of Methyl Pyropheophorbide-a-Mediated Photodynamic Therapy was Achieved by Increasing ROS through Inhibition of Nrf2-HO-1 or Nrf2-ABCG2 Signaling.
abstract: Emerging evidence indicates that the transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays an essential role in cellular defense against oxidative stress; its activation has been related to cytoprotection.
  
  
  
  Here, we investigated the role of Nrf2 in improving the efficacy of methyl pyropheophorbide-amediated photodynamic therapy (Mppa-PDT) via the downregulation of Nrf2.
  
  
  
  Human ovarian cancer A2780 cells and SKOV3 cells were treated with Mppa-PDT and siRNA transfection was performed to inhibit Nrf2. After treated with siRNA and Mppa-PDT, the cell viability was examined with CCK-8 assay; cell apoptosis was detected tested by flow cytometry with Annexin V-FITC/PI; the celluar reactive oxygen species (ROS) and mitochondrial membrane potential were measured with DCFHDA and JC-1 staining; expression of protein was assessed by western blot analysis.
  
  
  
  We found that Nrf2 translocated from the cytoplasm to the nucleus in vitro and in vivo, and the expression of Nrf2 and P-Nrf2 increased through a possible mechanism regulated by mitogen-activated protein kinase (MAPK) after Mppa-PDT treatment. Furthermore, cytotoxicity and apoptosis induced by Mppa-PDT increased after Nrf2down-regulation. Nrf2 down -regulation increased reactive oxygen species (ROS) levels by attenuating antioxidants or pumping Mppa out of cells,which resulted from the inhibition of Nrf2-HO-1 or Nrf2- ABCG2 signaling. In addition, SKOV3 cells exhibited increased resistance to Mppa-PDT, and the expression levels of P-Nrf2 and ABCG2 were higher in SKOV3 cells than in A2780 cells, suggesting that Nrf2-ABCG2 signaling might be involved in the intrinsic resistanceto Mppa-PDT.
  
  
  
  These results provided evidence that Nrf2 down-regulation can enhance the effect of Mppa-PDT.
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Si
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yong
authors.affiliation: Department of Rehabilitation Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Kai-Ting
authors.initials: KT
authors.lastname: Li
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kong
authors.affiliation: Department of Rehabilitation Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Ting-He
authors.initials: TH
authors.lastname: Yu
authors.affiliation: Department of Rehabilitation Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Le-Hua
authors.initials: LH
authors.lastname: Yu
authors.affiliation: Department of Rehabilitation Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing. China.
authors.forename: Ding-Qun
authors.initials: DQ
authors.lastname: Bai
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010778:Photochemotherapy / Q000379:methods*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D002734:Chlorophyll; C040298:pyropheophorbide a; D006419:Heme Oxygenase (Decyclizing)
keywords: ABCG2; HO-1; Nrf2; P-Nrf2; PDT; ROS