c-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells

Abstract Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh cause of cancer deaths worldwide. Mutations in the KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with cell cycle deregulation, apoptosis inhibition, invasion, metastasis, and poor treatment outcomes in PC. The standard therapy for PC is gemcitabine, nab-paclitaxel, and FOLFIRINOX, however, they have poor survival rates. Therefore, optimizing therapy for patients with PC is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer. Accordingly, here we investigated their cellular mechanism of action, with a particular focus on the proteins frequently mutated in PC. We showed that apoptosis was the main triggered mechanism of death and the induction of SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets for UAs can ease the induction of cell death in the p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. What is remarkable, senescent cells after prolonged exposition to UAs can die by apoptosis. Thus, UAs exhibit desirable features of promising candidates for future pancreatic cancer therapies.