Fig. 7: Targeted inhibition of NOX activation and glutathione biosynthesis for treating mutant RAS-harboring cancers.

A Oncogenic RAS activation enhances both ROS-generating NOX and ROS-scavenging glutathione biosynthesis to induce a higher level of redox balance for optimal survival and proliferation of cancer cells. B NOX catalyzes the oxidation of NADPH to NADP⁺, leading to the generation of O₂⁻ by the reduction of molecule oxygen (O₂). O₂⁻ can be converted to other forms of reactive oxygen species (ROS), the levels of which can be regulated by the reduced glutathione and glutathione-coupled antioxidant enzymes. Normal cells keep the ROS and antioxidant capacity at basal levels. However, oncogenic RAS activates NOX activity, leading to an increase in ROS generation. It also upregulates GCL and other enzymes in glutathione biosynthesis, leading to an elevated cellular glutathione pool. As a result, the heightened oxidative stress and antioxidant capability, at a certain threshold with an adequate range, achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation in adverse conditions. On the other hand, the coexistence of both elevated redox arms irrevocably creates a vulnerability and, thus, an opportunity for the targeted therapy, as exemplified by the combined DPI and BSO treatment in this study. Exogenous NAC can, directly and indirectly, replenish the reduced cellular glutathione pool to significantly attenuate the cytotoxic effects of the combination therapy.