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 Drakos, E. Articles by Rassidakis, G. Z. Search for Related Content PubMed PubMed Citation Articles by Drakos, E. Articles by Rassidakis, G. Z.

Inhibition of p53-Murine Double Minute 2 Interaction by Nutlin-3A Stabilizes p53 and Induces Cell Cycle Arrest and Apoptosis in Hodgkin Lymphoma

Authors' Affiliations: Departments of ¹ Hematopathology and ² Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: George Z. Rassidakis, Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Unit 54, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2535; Fax: 713-792-7273; E-mail: gzrassidakis{at}mdanderson.org.

Purpose: p53 is frequently expressed but rarely mutated in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL). p53 protein levels are regulated by murine double minute 2 (MDM2) through a well-established autoregulatory feedback loop. In this study, we investigated the effects of nutlin-3A, a recently developed small molecule that antagonizes MDM2 and disrupts the p53-MDM2 interaction, on p53-dependent cell cycle arrest and apoptosis in cultured HRS cells.

Experimental Design: HL cell lines carrying wild-type (wt) or mutated p53 gene were treated with the potent MDM2 inhibitor nutlin-3A or a 150-fold less active enantiomer, nutlin-3B.

Results: We show that nutlin-3A, but not nutlin-3B, stabilizes p53 in cultured HRS cells carrying wt p53 gene resulting in p53-dependent cell cycle arrest and apoptosis. Cell cycle arrest was associated with up-regulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3A–induced apoptotic cell death was accompanied by Bax and Puma up-regulation and caspase-3 cleavage and was abrogated, in part, by inhibition of caspase-9 and caspase-3 activity. By contrast, no effects on cell cycle or apoptosis were found in HL cell lines harboring mutated p53 gene. Furthermore, combined treatment with nutlin-3A and doxorubicin revealed enhanced cytotoxicity in HRS cells with wt p53 gene. Blocking of nuclear export by leptomycin B, or inhibition of proteasome by MG132, stabilized p53 at a level comparable with that of nutlin-3A treatment in HRS cells with wt p53.

Conclusions: These data suggest that nutlin-3A stabilized p53 by preventing MDM2-mediated p53 degradation in HRS cells. wt p53 stabilization and activation by nutlin-3A may be a novel therapeutic approach for patients with HL.

This article has been cited by other articles:

				M. Miyachi, N. Kakazu, S. Yagyu, Y. Katsumi, S. Tsubai-Shimizu, K. Kikuchi, K. Tsuchiya, T. Iehara, and H. Hosoi Restoration of p53 Pathway by Nutlin-3 Induces Cell Cycle Arrest and Apoptosis in Human Rhabdomyosarcoma Cells Clin. Cancer Res., June 15, 2009; 15(12): 4077 - 4084. [Abstract] [Full Text] [PDF]

				P. Secchiero, E. Melloni, M. G. di Iasio, M. Tiribelli, E. Rimondi, F. Corallini, V. Gattei, and G. Zauli Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism Blood, April 30, 2009; 113(18): 4300 - 4308. [Abstract] [Full Text] [PDF]

				Y. Tabe, D. Sebasigari, L. Jin, M. Rudelius, T. Davies-Hill, K. Miyake, T. Miida, S. Pittaluga, and M. Raffeld MDM2 Antagonist Nutlin-3 Displays Antiproliferative and Proapoptotic Activity in Mantle Cell Lymphoma Clin. Cancer Res., February 1, 2009; 15(3): 933 - 942. [Abstract] [Full Text] [PDF]

				M. Wade and G. M. Wahl Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry? Mol. Cancer Res., January 1, 2009; 7(1): 1 - 11. [Abstract] [Full Text] [PDF]

				S. Shangary and S. Wang Targeting the MDM2-p53 Interaction for Cancer Therapy Clin. Cancer Res., September 1, 2008; 14(17): 5318 - 5324. [Abstract] [Full Text] [PDF]

				R. J. Jones, Q. Chen, P. M. Voorhees, K. H. Young, N. Bruey-Sedano, D. Yang, and R. Z. Orlowski Inhibition of the p53 E3 Ligase HDM-2 Induces Apoptosis and DNA Damage-Independent p53 Phosphorylation in Mantle Cell Lymphoma Clin. Cancer Res., September 1, 2008; 14(17): 5416 - 5425. [Abstract] [Full Text] [PDF]

				N. Zhu, L. Gu, F. Li, and M. Zhou Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1101 - 1109. [Abstract] [Full Text] [PDF]