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

Giuseppe Montalto, Melchiorre Cervello, Weifeng Mao, Alberto M. Martelli, Saverio Candido, Bruno Bueno-Silva, Stefano Ratti, Heng-Liang Lin, Agnieska Gizak, Kvin Lertpiriyapong, Dariusz Rakus, Pedro L. Rosalen, Massimo Libra, Severino Matias De Alencar, Shaw M. Akula, Linda S. Steelman, James A. Mccubrey, Paolo Lombardi, Ramiro M. Murata, Lucio CoccoGiuseppe Montalto, Matilde Y. Follo, Stephen L. Abrams

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Abstract

Mutations 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 in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-TP53, as well as, the effects that the MDM2 inhibitor nutlin-3a can have in both cells containing and lacking WT-TP53 to various therapeutic agents.
Lingua originaleEnglish
pagine (da-a)22-40
Numero di pagine19
RivistaAdvances in Biological Regulation
Volume72
Stato di pubblicazionePublished - 2019

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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Montalto, G., Cervello, M., Mao, W., Martelli, A. M., Candido, S., Bueno-Silva, B., Ratti, S., Lin, H-L., Gizak, A., Lertpiriyapong, K., Rakus, D., Rosalen, P. L., Libra, M., De Alencar, S. M., Akula, S. M., Steelman, L. S., Mccubrey, J. A., Lombardi, P., Murata, R. M., ... Abrams, S. L. (2019). 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. Advances in Biological Regulation, 72, 22-40.