This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barbieri, E. Articles by Shohet, J. M. Search for Related Content PubMed PubMed Citation Articles by Barbieri, E. Articles by Shohet, J. M.

Research Articles: Therapeutics

MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death

¹ Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas and ² Department Hematology-Oncology, University of Bologna, Bologna, Italy

Requests for reprints: Jason M. Shohet, Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston TX 77030. Phone: 832-824-4723; Fax: 832-825-4732. E-mail: jmshohet{at}texachildrenshospital.org

Novel therapeutic approaches are urgently needed for high-stage neuroblastoma, a major therapeutic challenge in pediatric oncology. The majority of neuroblastoma tumors are p53 wild type with intact downstream p53 signaling pathways. We hypothesize that stabilization of p53 would sensitize this aggressive tumor to genotoxic chemotherapy via inhibition of MDM2, the primary negative upstream regulator of p53. We used pharmacologic inhibition of the MDM2-p53 interaction with the small-molecule inhibitor Nutlin and studied the subsequent response to chemotherapy in neuroblastoma cell lines. We did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase assays to measure proliferation and apoptosis in several cell lines (IMR32, MYCN3, and JF) treated with combinations of cisplatin, etoposide, and Nutlin. We found consistent and robust decreases in proliferation and increases in apoptosis with the addition of Nutlin 3a to etoposide or cisplatin in all cell lines tested and no response to the inactive Nutlin 3b enantiomer. We also show a rapid and robust accumulation of p53 protein by Western blot in these cells within 1 to 2 hours of treatment. We conclude that MDM2 inhibition dramatically enhances the activity of genotoxic drugs in neuroblastoma and should be considered as an adjuvant to chemotherapy for this aggressive pediatric cancer and for possibly other p53 wild-type solid tumors. [Mol Cancer Ther 2006;5(9):2358–65]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: E. Barbieri and P. Mehta contributed equally to this work.

³ Dr. Michael Hogarty, Children's Hospital of Philadelphia, personal communication.

Received 5/23/06; revised 7/ 7/06; accepted 7/26/06.

This article has been cited by other articles:

				H. S. Bell and K. M. Ryan iASPP Inhibition: Increased Options in Targeting the p53 Family for Cancer Therapy Cancer Res., July 1, 2008; 68(13): 4959 - 4962. [Abstract] [Full Text] [PDF]

				C. E. Kan, J. T. Patton, G. R. Stark, and M. W. Jackson p53-Mediated Growth Suppression in Response to Nutlin-3 in Cyclin D1 Transformed Cells Occurs Independently of p21 Cancer Res., October 15, 2007; 67(20): 9862 - 9868. [Abstract] [Full Text] [PDF]

				A. Efeyan, A. Ortega-Molina, S. Velasco-Miguel, D. Herranz, L. T. Vassilev, and M. Serrano Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin Cancer Res., August 1, 2007; 67(15): 7350 - 7357. [Abstract] [Full Text] [PDF]

				A. D. Slack, Z. Chen, A. D. Ludwig, J. Hicks, and J. M. Shohet MYCN-Directed Centrosome Amplification Requires MDM2-Mediated Suppression of p53 Activity in Neuroblastoma Cells Cancer Res., March 15, 2007; 67(6): 2448 - 2455. [Abstract] [Full Text] [PDF]