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Enhancement of antioxidant capacity by novel dithiolethiones as a consequence of Fyn inhibition
Author(s) -
Koo Ja Hyun,
Lee Woo Hyung,
Kim Sang Geon
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.839.2
Subject(s) - fyn , ampk , chemistry , mitochondrion , microbiology and biotechnology , antioxidant , malondialdehyde , oxidative phosphorylation , viability assay , phosphorylation , biochemistry , protein kinase a , cell , biology , proto oncogene tyrosine protein kinase src
Fyn has emerged as a regulator of diverse pathological processes. However, the inhibitor is clinically available. This study investigated the potential of cycloalkane‐fused or other dithiolethiones in increasing antioxidant capacity in association with Fyn inhibition and the molecular basis for this effect. Treatment of HepG2 cells with each agent protected mitochondria from oxidative injury, increasing cell viability; 4,5,6,7‐tetrahydrobenzo‐1,2‐dithiole‐3‐thione (SNU1A) and 5,6‐dihydro‐4H‐cyclopenta‐1,2‐dithiole‐3‐thione were the most effective, whereas 5‐methyl‐1,2‐dithiole‐3‐thione was intermediate. 5‐(Quinolin‐2‐yl)‐1,2‐dithiole‐3‐thione was the least active. SNU1A treatment decreased mitochondrial superoxide production, and restored mitochondrial membrane permeability. Oxidative injury enhanced Fyn phosphorylation, which was diminished by SNU1A. Fyn inhibition contributed to the protection of mitochondria through AMPK, as supported by Fyn's reversal of the effect. Consistently, Fyn overexpression antagonized AMPK activation by SNU1A, strengthening the inhibitory regulation of Fyn on AMPK. SNU1A and congeners had an antioxidant effect and additionally activated Nrf2. In summary, the new dithiolethiones have antioxidant and cytoprotective effect, which may result not only from Fyn inhibition leading to AMPK activation, but from Nrf2 activation.