Publication:
Suppression of Nrf2 confers chemosensitizing effect through enhanced oxidant-mediated mitochondrial dysfunction

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Issued Date

2018

Resource Type

Article

File Type

application/pdf

ISSN

7533322

DOI

10.1016/j.biopha.2018.02.112

Other identifier(s)

2-s2.0-85042862855

Rights Holder(s)

Scopus

Bibliographic Citation

Biomedicine and Pharmacotherapy. Vol 101, (2018), p.627-634

Suggested Citation

Sompakdee V., Prawan A., Senggunprai L., Kukongviriyapan U., Samathiwat P., Wandee J., Kukongviriyapan V. Suppression of Nrf2 confers chemosensitizing effect through enhanced oxidant-mediated mitochondrial dysfunction. Biomedicine and Pharmacotherapy. Vol 101, (2018), p.627-634. doi:10.1016/j.biopha.2018.02.112 Retrieved from: https://hdl.handle.net/20.500.14740/5555

Title

Suppression of Nrf2 confers chemosensitizing effect through enhanced oxidant-mediated mitochondrial dysfunction

Author(s)

Sompakdee V.
 Prawan A.
 Senggunprai L.
 Kukongviriyapan U.
 Samathiwat P.
 Wandee J.
 Kukongviriyapan V.

Abstract

Aims: Transcription factor Nrf2, which regulates the expression of cytoprotective and antioxidant enzymes, contributes to proliferation and resistance to chemotherapy in cancer. The inhibition of Nrf2 can sensitize cholangiocarcinoma (CCA) cells to the cytotoxicity of several chemotherapeutic agents. In this study, we investigated the mechanism of this chemosensitizing effect. Main methods: KKU-100 cells were used in the study. Nrf2 expression was knocked down by siRNA and expression was validated by reverse transcription and polymerase chain reaction. Cytotoxicity was assessed by sulforhodamine B method. Intracellular reactive oxygen species (ROS) was examined by fluorescent dye, dichlorofluorescin diacetate method and mitochondrial transmembrane potential was assessed by JC1 dye assay. Key findings: Cytotoxicity of cisplatin (Cis) in KKU-100 cells was enhanced by knockdown of Nrf2 expression. The enhanced cytotoxic effect was abolished by treatment with N-acetylcysteine, TEMPOL and MnTBAP. Cells with Nrf2 knockdown or Cis treatment increased production of ROS, and ROS was markedly enhanced by a combination of Nrf2 knockdown and Cis. The increased ROS formation was associated with a decrease in mitochondrial transmembrane potential (Δψm), where this decrease was prevented by antioxidant compounds. The loss of Δψm and cell death were prevented by cyclosporine, an inhibitor of mitochondrial permeability transition pore (MPTP). Luteolin inhibited Nrf2 and markedly enhanced cytotoxicity in combination with Cis. Significance: Inhibition of Nrf2 is a feasible strategy in enhancing antitumor activity of chemotherapeutic agents and improving efficacy of chemotherapy in CCA. © 2018 Elsevier Masson SAS

Subject(s)

Acetylcysteine
 Cisplatin
 Cyclosporine
 Dichlorodihydrofluorescein diacetate
 Fluorescent dye
 Luteolin
 Reactive oxygen metabolite
 Small interfering RNA
 Sulforhodamine B
 Tempol
 Transcription factor Nrf2
 [5,10,15,20 tetrakis(4 carboxyphenyl) 21h,23h porphine]manganese(iii) chloride
 Antineoplastic agent
 Cisplatin
 NFE2L2 protein, human
 Oxidizing agent
 Transcription factor Nrf2
 Article
 Bile duct carcinoma
 Cell death
 Chemosensitization
 Controlled study
 Cytotoxicity
 Disorders of mitochondrial functions
 Drug cytotoxicity
 Drug mechanism
 Human
 Human cell
 Human tissue
 KKU-100 cell line
 Mitochondrial membrane potential
 Oxidative stress
 Priority journal
 Protein expression
 Reverse transcription polymerase chain reaction
 Antagonists and inhibitors
 Drug effect
 Gene knockdown
 Metabolism
 Mitochondrion
 Physiology
 Procedures
 Tumor cell line
 Antineoplastic Agents
 Cell Line, Tumor
 Cisplatin
 Gene Knockdown Techniques
 Humans
 Membrane Potential, Mitochondrial
 Mitochondria
 NF-E2-Related Factor 2
 Oxidants
 Reactive Oxygen Species

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URI

https://hdl.handle.net/20.500.14740/5555

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Scopus: Year 1983-2021

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