Recent Advances in the Therapeutic Perspectives of Nutlin-3

Paola      Secchiero; Raffaella      Bosco; Claudio      Celeghini; Giorgio      Zauli

Abstract

Nutlin-3 is a small molecule inhibitor of the MDM2/p53 interaction, which leads to the non-genotoxic p53 stabilization, activation of cell cycle arrest and apoptosis pathways. A series of recent studies have strengthened the concept that selective, non-genotoxic p53 activation by Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy, in particular for pediatric tumors and for hematological malignancies, which retain a high percentage of p53wild-type status at diagnosis. Like most other drugs employed in cancer therapy, it will be unlikely that Nutlin-3 will be used as a monotherapy. In this respect, Nutlin-3 shows a synergistic cytotoxic effect when used in combination with innovative drugs, such as TRAIL or bortozemib. Although Nutlin-3 is currently in phase I clinical trial for the treatment of retinoblastoma, its effects on normal tissues and cell types remain largely to be determined and will require further investigation in the future years.

Keywords: Pediatric malignancies, hematological malignancies, p53 pathway, apoptosis, senescence, therapeutic combinations, Nutlin-3, MDM2, HDM2, PEDIATRIC TUMORS, chemotherapy, malignancies, P-gp, p53-independent, leukemia, synergistic, endothelial, autophagic, pharmacokinetics