Activated O2 •-and H2O2mediated cell survival in SU11274-treated non-small-cell lung cancer A549 cells via c-Met-PI3K-Akt and c-Met-Grb2/SOS-Ras-p38 pathways

The pharmacological activity of su11274 is primarily due to its inhibition of hepotocyte growth factor receptor (c-met) kinase overexpression. in this study,we demonstrated that the pathway involved in su11274-induced autophagy was presumably through inhibition of c-met and its down-stream pathways,including phosphatidylinositol 3-kinases - akt (pi3k-akt) and the growth factor receptor bound protein-2 / son of sevenless - ras - p38 mapk (grb2/sos-ras-p38) pathway. su11274 time-dependently induced the generation of superoxide anion (o2 •-) and hydrogen peroxide (h2o2). there is a negative feedback loop between reactive oxygen species (ros) induction and su11274. then,we investigated the role of ros in protecting cells against su11274-induced autophagic cell death in a549 cells. o2 •-and h2o2generation activated c-met-pi3k-akt and c-met-grb2/sos-ras-p38 signaling pathways,which were suppressed by o2 •-scavenger superoxide dismutase (sod) and h2o2scavenger catalase. in conclusion,o2 •-and h2o2evoked cell resistance to su11274 via activating c-met-pi3k-akt and c-met-grb2/sos-ras-p38 pathways in a549 cells. su11274 also induced ros generation in caenorhabditis elegans. © the japanese pharmacological society.