Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals

Publication date: Available online 15 March 2019Source: Advances in Biological RegulationAuthor(s): Saverio Candido, Stephen L. Abrams, Linda S. Steelman, Kvin Lertpiriyapong, Alberto M. Martelli, Lucio Cocco, Stefano Ratti, Matilde Y. Follo, Ramiro M. Murata, Pedro L. Rosalen, Bruno Bueno-Silva, Severino Matias de Alencar, Paolo Lombardi, Weifeng Mao, Giuseppe Montalto, Melchiorre Cervello, Dariusz Rakus, Agnieska Gizak, Heng-Liang Lin, Massimo LibraAbstractMutations at the TP53 gene are readily detected (approximately 50–75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted...
Source: Advances in Biological Regulation - Category: Biology Source Type: research