As proof of concept, we found that OPH depletes GSH in the presence of S NPAA in vitro as well as in cell lines overexpressing OPH. Additionally, we found that S NPAA, when activated selleck compound by OPH, is effective at increasing oxidative stress, inducing apoptosis, and decreasing cell viability in tumori genic prostate cancer cells while having only minimal such effects on a nontumorigenic Inhibitors,Modulators,Libraries prostate epithelial cell line. As outlined in Figure 9, the work presented here suggests that S NPAA can exploit a newly recognized weakness in one of the signaling pathways that cancer cells utilize to maintain an aggressive cancer phenotype, i. e, a high level of intrinsic oxidative stress due to the activation of the Akt kinase cascade.

Akt kinase is a master compo nent of the signaling cascades critical Inhibitors,Modulators,Libraries for regulating cell survival, cell growth, glucose metabolism, cell motility and angiogenesis. Constitutive Akt activation is caused by mutations in components of its signaling cascade and results in cancer cells with an increased ability to escape apoptosis and proliferate. Moreover, Akt activation results in an increased production of cellular ROS which plays a causal role in maintaining many cancer phenotypes. This, however, is a double edged sword since the in creased ROS production resulting from continuous Akt activation also results in an increased sensitivity to pro oxidant drugs that can tip cancer cells into apoptosis. We recently reported that OPH is overexpressed in the human LNCaP tumorigenic prostate cell line compared to control human RWPE 1 prostate epithelial cells.

In the work reported here, Inhibitors,Modulators,Libraries we found that lysates from tumorigenic LNCaP cells were more ef fective at in vitro GSH depletion than non tumorigenic RWPE 1 cell lysates. The higher degree of GSH depletion in LNCaP cells is consistent with the over expression of OPH found in these cells compared with that observed in the Inhibitors,Modulators,Libraries RWPE 1 cells. LNCaP and COS 7 OPH cells treated with S NPAA were also found to have a greater depletion of intracellular Inhibitors,Modulators,Libraries GSH as well as a Erlotinib mechanism greater loss of cell viability than similarly treated RWPE 1 and COS 7 cells. Collect ively, our preclinical findings are significant since they potentially provide a molecular basis for potentially selecting those cancer patients most likely to respond to S NPAA like prodrugs, i. e, those with activated Akt and OPH overexpression. While a high OPH activity contributes to the effectiveness of the S NPAA prodrug, it is also plausible that a high level of basal cellular oxidative stress would similarly contribute to inhibiting cell growth even in the face of normal OPH activity.