Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. In ~75% of PDAC, the tumor suppressor TP53 gene is mutated. Novel approaches to treat cancer involve compounds called mutant TP53 reactivators. They interact with mutant TP53 proteins and restore some of their growth suppressive properties, but they may also interact with other proteins, e.g., TP63 and TP73. We examined the ability of the TP53 reactivator APR-246 to interact with eleven modified berberine compounds (NAX compounds) in the presence and absence of WT-TP53 in two PDAC cell lines: the MIA-PaCa-2, which has gain of function (GOF) TP53 mutations on both alleles, and PANC-28, which lacks expression of the WT TP53 protein. Our results indicate the TP53 reactivator-induced increase in therapeutic potential of many modified berberines.
Highlights
Pancreatic cancer is the second leading cause of death [1,2]
Identification of low molecular weight TP53 activators that interact with the mutant TP53 protein and restore some of its activity provide an approach to suppress the effects of gain of function (GOF) TP53 mutations [25–27]
APR-246 to increase the abilities of BBR and NAX compounds to inhibit the proliferation of two pancreatic ductal adenocarcinomas (PDAC) cell lines, one of which has GOF mutations in the p53 protein and 26 the other of which is TP53 null, before and after introduction of WT-TP53
Summary
Pancreatic cancer is the second leading cause of death [1,2]. Most pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC) [1–3]. Point mutations at the TP53 gene may result in a protein with an altered activity in comparison to the WT protein In some cases, these mutant TP53 proteins may have altered growth regulatory properties and diverse biochemical effects. Identification of low molecular weight TP53 activators (reactivators) that interact with the mutant TP53 protein and restore some of its activity provide an approach to suppress the effects of GOF TP53 mutations [25–27]. BBR treatment can result in the production of reactive oxygen species (ROS) [49,52], induction of autophagy, apoptosis, and cellular senescence, suppression of events associated with migration and metastasis such as inhibition of cytokine/chemokine expression, APR-246 to increase the abilities of BBR and NAX compounds to inhibit the proliferation of two PDAC cell lines, one of which has GOF mutations in the p53 protein and 3 of. Berberine; mutant TP53; green arrows, promote activity; red arrows, block activity; red X in arrow, activity is blocked
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