Preclinical Pharmacology of the MDM2 Antagonist Nutlin-3a
type: CreativeWork
description: Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues. Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of nutlin-3a on the cell viability of neuroblastoma both as a single agent and in combination with topotecan. We showed that targeting MDM2-p53 interaction using nutlin-3a reduced cell growth in neuroblastoma cells. p53 wild-type cells were much more sensitive to nutlin-3a treatment compared to p53 mutant cells. When nutlin-3a was combined with topotecan, a synergistic effect on neuroblastoma cell growth was observed. To explore the mechanism of synergy, we performed quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis and found reduction of P-gp expression at both the message level and protein level in p53 wild-type neuroblastoma cells. This is the first study showing the synergistic effect of nutlin-3a in combination with topotecan in neuroblastoma cells and the reduction of P-gp expression by nutlin-3a in p53 wild-type cells. Although nutlin-3a is currently under pre-clinical investigation as a p53 reactivation agent, it has been recently demonstrated also to have p53 independent actions in cancer cells. In the second part of the study, we first reported that nutlin-3a can inhibit the efflux function of BCRP. We observed that although the nutlin-3a IC50 did not differ between BCRP over-expressing and vector control cells, nutlin-3a treatment sig…
abstract: Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues. Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of nutlin-3a on the cell viability of neuroblastoma both as a single agent and in combination with topotecan. We showed that targeting MDM2-p53 interaction using nutlin-3a reduced cell growth in neuroblastoma cells. p53 wild-type cells were much more sensitive to nutlin-3a treatment compared to p53 mutant cells. When nutlin-3a was combined with topotecan, a synergistic effect on neuroblastoma cell growth was observed. To explore the mechanism of synergy, we performed quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis and found reduction of P-gp expression at both the message level and protein level in p53 wild-type neuroblastoma cells. This is the first study showing the synergistic effect of nutlin-3a in combination with topotecan in neuroblastoma cells and the reduction of P-gp expression by nutlin-3a in p53 wild-type cells. Although nutlin-3a is currently under pre-clinical investigation as a p53 reactivation agent, it has been recently demonstrated also to have p53 independent actions in cancer cells. In the second part of the study, we first reported that nutlin-3a can inhibit the efflux function of BCRP. We observed that although the nutlin-3a IC50 did not differ between BCRP over-expressing and vector control cells, nutlin-3a treatment sig…
author: Zhang, Fan
keywords: ABC transporter, BCRP, Nutlin-3a, Pharmacokinetics, PBPK, Medicinal and Pharmaceutical Chemistry, Medicine and Health Sciences, Pharmaceutics and Drug Design, Pharmacy and Pharmaceutical Sciences
date published: 2011-12-01T08:00:00Z
date modified: 2026-07-24T05:00:23Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center