4.4 Article

2,2′-Dipyridyl diselenide (Py2Se2) induces G1 arrest and apoptosis in human lung carcinoma (A549) cells through ROS scavenging and reductive stress

Journal

METALLOMICS
Volume 12, Issue 8, Pages 1253-1266

Publisher

OXFORD UNIV PRESS
DOI: 10.1039/d0mt00106f

Keywords

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Funding

  1. Chemistry Group, BARC

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Organo-diselenides are well documented for pro-oxidant effects in tumor cells. However, the present study demonstrated that 2,2 '-dipyridyl diselenide (Py2Se2) induced cytotoxicity in human non-small cell lung carcinoma (A549) cells through reductive stress marked by a significant decrease in the basal level of reactive oxygen species and a concurrent decrease in the ratio of oxidised (GSSG) and reduced (GSH) glutathione. The IC50(concentration inducing 50% cytotoxicity) ofPy(2)Se(2)in A549 and human normal lung fibroblast (WI38) cells was similar to 8.5 mu M and similar to 5.5 mu M, respectively, indicating thatPy(2)Se(2)did not exhibit selective toxicity towards cancer cells. Cell free studies indicated thatPy(2)Se(2)acted as a substrate of thioredoxin reductase (TrxR) and accordingly it was proposed that TrxR mediated reduction ofPy(2)Se(2)within cells might be generating intermediates leading to a reductive environment. Despite generating a reducing environment,Py(2)Se(2)caused significant DNA damage, G1 phase arrest and apoptosis. The mechanistic investigation revealed thatPy(2)Se(2)induced G1 arrest was mediated through up-regulation of p21 transcript in a p53 independent manner. Further, the apoptotic effect ofPy(2)Se(2)was associated with the increase in the levels of unfolded protein response markers like BiP and CHOP, mitochondrial permeability (JC1) and apoptotic markers such as cleaved caspase-3 and poly (ADP-ribose) polymerase. Finally, pre-treatment withN-acetylcysteine (a stimulator of GSH biosynthesis) orl-buthionine sulfoximine (an inhibitor of GSH biosynthesis) increased and decreased thePy(2)Se(2)mediated apoptosis, respectively. This confirmed that the cytotoxicity ofPy(2)Se(2)in A549 cells was triggered through reductive stress.

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