Proposed model of the selective killing of
–transformed cells by NOX inhibition. K-ras transformation causes the activation of the downstream effector, phosphatidylinositol 3′-kinase (PI3K). Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the lipid product of a PI3K-catalyzed reaction, enhances the guanine-nucleotide exchange factor (GEF) activity that mediates the exchange of Rac-GDP for Rac-GTP, and provides the lipid necessary for NOX subunit (p40phox) binding upon the translocation to the membrane, therefore causing the activation of NOX. NOX-induced ROS production stimulates cell proliferation and contributes to tumor progression. NOX inhibitor targets the activated NOX and causes excessive ROS generation, leading to cancer cell death. +, activation by the upstream effectors.