Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors
The p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments.\n\nPancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds poorly to the existing therapies and has very low overall survival rates.\n\nHere, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. Our findings, may contribute to faster repurposing of PpIX and BPD to treat pancreatic tumors.\n\nLay AbstractDespite the efforts, pancreatic cancer remains among the most aggressive tumors. Late diagnoses often linked with the asymptomatic disease progression make it extremely difficult to cure. We have used drugs that are already in clinics and applied in photodynamic therapy of cancer and showed that the compounds induce death of cancer cells. The mechanism is via activation of p73 tumor suppressor and inhibition oncogenic thioredoxin reductase. Molecules that in parallel induce two pathways leading to cell death might be very promising candidates for improved cancer therapy in pancreatic cancer patients.