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

Author(s): Si Tian, Min Yong, Jiang Zhu, Li Zhang, Li Pan, Qing Chen, Kai-Ting Li, Yu-Han Kong , Yuan Jiang, Ting-He Yu, Le-Hua Yu, Ding-Qun Bai*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , Issue 13 , 2017

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Abstract:

Background: 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.

Objective: Here, we investigated the role of Nrf2 in improving the efficacy of methyl pyropheophorbide-amediated photodynamic therapy (Mppa-PDT) via the downregulation of Nrf2.

Method: 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.

Results: 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.

Conclusion: These results provided evidence that Nrf2 down-regulation can enhance the effect of Mppa-PDT.

Keywords: PDT, ROS, Nrf2, ABCG2, HO-1, P-Nrf2.

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Article Details

VOLUME: 17
ISSUE: 13
Year: 2017
Page: [1824 - 1836]
Pages: 13
DOI: 10.2174/1871520617666170327145857
Price: $58

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