APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells
James Andrew McCubrey,
Stephen L. Abrams,
Linda S. Steelman,
Lucio Cocco,
Stefano Ratti,
Alberto M. Martelli,
Paolo Lombardi,
Agnieszka Gizak,
Przemysław Duda
Affiliations
James Andrew McCubrey
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
Stephen L. Abrams
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
Linda S. Steelman
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
Lucio Cocco
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Stefano Ratti
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Alberto M. Martelli
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Paolo Lombardi
Naxospharma, Via Giuseppe Di Vittorio 70, 20026 Novate Milanese, Italy
Agnieszka Gizak
Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wroclaw, Poland
Przemysław Duda
Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wroclaw, Poland
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.
