Mitochondrial Targeted Curcumin Inhibits Glutathione Reductase and Modulates Mitochondrial Redox: A Potential Novel Strategy for the Treatment of Resistant NSCLC

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Background: The dedicated thioredoxin and glutathione redox systems are the central antioxidant defense mechanisms by which mitochondria neutralize the excess ROS. In cancer, these antioxidant systems get upregulated to cope with oxidative stress insult caused due to dysfunctional mitochondria. These upregulated antioxidant systems lead to drug resistance in lung cancer.

Materials and Methods: The cytotoxicity of mitocurcuminin A549 cells at different time points and its IC₅₀ was calculated by MTT assay. Cell-free and cell-based glutathione reductase (GR) inhibition was studied by DTNB reduction assay. Autodockvina and LigPlot tools were used for molecular docking and ligand interaction studies.

Results: Mitocurcumin exhibited cytotoxicity on A549 cells with IC₅₀ of 7.91, 5.37, and 3.37 μM at 24, 48, and 72 hours, respectively. It inhibited recombinant GR in cell-free system with IC₅₀ of 1.27 μM and mitochondrial GR in A549 cells. GR inhibition was independent of NADPH which serves as the cofactor in enzyme catalysis and showed mixed-II-type inhibition where Km and Vmax both decreased. The inhibition of GR-affected mitochondrial and cellular GSH pool by increasing both mitochondrial and cellular ROS in a dose- and time-dependent manner. In silico-docking studies revealed that mitocurcumin binds to the site other than active site of GR.

Conclusion: Mitocurcumin affects proliferation of A549 cells in dose- and time-dependent manner. It inhibits GR in cell-free system and in A549 cells which in turn modulates mitochondrial redox leading to ROS dependent apoptosis in A549 cells.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
22 August 2022