Targeting cellular redox modulations for pancreatic cancer treatment

Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered two novel classes of compounds, triphenylphosphoniums and quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling ( This dissertation mainly focuses on quinazolinediones).;Compound 3a was identified through a medium throughput screen of ∼1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analogue, 3b that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. Since our compounds exert Akt-dependent ROS-mediated cell death, they may provide potential therapeutic options for chemoresistant and Akt-overexpressing cancers.;Pancreatic cancer is a complex disease characterized by alterations in several key regulators of signaling pathways. Increased expression and activity of Src and FAK have been observed in pancreatic cancer and linked to its inherent and acquired chemoresistance. Sustained Src inhibition leads to reactivation of survival pathways regulated by STAT3 resulting in resistant forms of cancer. Therefore, targeting the Src/FAK axis could provide an important strategy for the treatment of pancreatic cancer. Mechanistic evaluation of compound 3b revealed that it potently decreases Src/FAK and STAT3 phosphorylation leading to inhibition of cancer cell migration and angiogenesis. Therefore, we named our lead compound 3b, sarkostat(TM). Furthermore, sarkostat arrests cell cycle progression and causes apoptotic cell death in cancer cells in low micromolar range. Additionally, sarkostat overcomes the limitations of Src inhibitors by decreasing STAT3 activity.;Simultaneous studies with triphenylphosphoniums (TPs) revealed their OCR decreasing effects in cancer cell lines. Interestingly, TPs also induced oxidative stress and activated stress kinases leading to apoptosis. Moreover, TPs inhibited Src/FAK complex and decreased cell migration and invasion in pancreatic cancer cells.;Lastly, we have studied one of the bystander effects of ROS generating therapy. Chemotherapy induced peripheral neuropathy is attributed to the oxidative stress and mitochondrial dysfunction resulting from chemotherapeutic agents. We have designed and synthesized novel redox modulators tagged to triphenylphosphonium moiety. Our novel mitochondrial targeted redox modulators exert protective antioxidant effects without interfering with the anticancer effects of chemodrugs. In conclusion, we have discovered and characterized promising agents with unique mechanism that shows great potential as a therapy for pancreatic cancer.