Correspondence to: vikramgota@gmail.com
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.
