Aims: REDOX signaling from
reactive oxygen species (ROS) generated by the mitochondria (mitochondrial
reactive oxygen species [mtROS]) has been implicated in
cancer growth and survival. Here, we investigated the effect of
5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human
lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human
lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of
lung cancer cell proliferation and triggered a reduction in
tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the
proteome of human
lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and
MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217
proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung
tumors. A unique dataset on proteomic reprogramming by AOL and
MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and
cancer signaling.