Recently we have reported potent anti-cancer actions of various steroidal Na+/K+ ATPase inhibitors in multiple cell lines.
Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly
effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo.
In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that
3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by
significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and
upregulation of c-Fos- gene transcription. In addition, the steroidal Na+/K+ ATPase inhibitor induced late de-phosphorylation of Focal
Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na+/K+ ATPase inhibitor 3-R-POD induces
apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, up-regulation of the
pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.