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MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy

Kojima, Kensuke ; Konopleva, Marina ; Samudio, Ismael J. ; Shikami, Masato ; Cabreira-Hansen, Maria ; McQueen, Teresa ; Ruvolo, Vivian ; Tsao, Twee ; Zeng, Zhihong ; Vassilev, Lyubomir T. ; Andreeff, Michael

Blood, 2005-11, Vol.106 (9), p.3150-3159 [Periódico revisado por pares]

Washington, DC: Elsevier Inc

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Título:
MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy
Autor: Kojima, Kensuke ; Konopleva, Marina ; Samudio, Ismael J. ; Shikami, Masato ; Cabreira-Hansen, Maria ; McQueen, Teresa ; Ruvolo, Vivian ; Tsao, Twee ; Zeng, Zhihong ; Vassilev, Lyubomir T. ; Andreeff, Michael
Assuntos: Adult ; Aged ; Antineoplastic agents ; Apoptosis - drug effects ; Biological and medical sciences ; Caspases - metabolism ; Cell Nucleus - metabolism ; Chemotherapy ; Cytoplasm - metabolism ; Doxorubicin - pharmacology ; Enzyme Activation - drug effects ; Female ; Hematologic and hematopoietic diseases ; Humans ; Imidazoles - pharmacology ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Leukemia, Myeloid, Acute - therapy ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical sciences ; Middle Aged ; Neoplasia ; Pharmacology. Drug treatments ; Piperazines - pharmacology ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53 - metabolism
É parte de: Blood, 2005-11, Vol.106 (9), p.3150-3159
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Prepublished online as Blood First Edition Paper, July 12, 2005; DOI 10.1182/blood-2005-02-0553.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.
Supported in part by National Institutes of Health grants PO1 CA55 164, PO1 CA49 639, and CA16 672 and the Paul and Mary Haas Chair in Genetics (M.A.); and by the Kanae Foundation for Life and Socio-Medical Science, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Uehara Memorial Foundation (K.K.).
Reprints: Michael Andreeff, Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 448, Houston, TX 77030; e-mail: mandreef@mdanderson.org.
L.T.V. is employed by Hoffman La-Roche Inc, whose potential product was studied in the present work.
Descrição: Although TP53 mutations are rare in acute myeloid leukemia (AML), inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulator MDM2 (murine double minute 2). Recently, small-molecule antagonists of MDM2, Nutlins, have been developed that inhibit the p53-MDM2 interaction and activate p53 signaling. Here, we study the effects of p53 activation by Nutlin-3 in AML cells. Treatment with MDM2 inhibitor triggered several molecular events consistent with induction of apoptosis: loss of mitochondrial membrane potential, caspase activation, phosphatidylserine externalization, and DNA fragmentation. There was a positive correlation in primary AML samples with wild-type p53 between baseline MDM2 protein levels and apoptosis induced by MDM2 inhibition. No induction of apoptosis was observed in AML samples harboring mutant p53. Colony formation of AML progenitors was inhibited in a dose-dependent fashion, whereas normal CD34+ progenitor cells were less affected. Mechanistic studies suggested that Nutlin-induced apoptosis was mediated by both transcriptional activation of proapoptotic Bcl-2 family proteins, and transcription-independent mitochondrial permeabilization resulting from mitochondrial p53 translocation. MDM2 inhibition synergistically enhanced cytotoxicity of cytosine arabinoside and doxorubicin in AML blasts but not in normal hematopoietic progenitor cells. p53 activation by targeting the p53-MDM2 interaction might offer a novel therapeutic strategy for AML that retain wild-type p53.
Editor: Washington, DC: Elsevier Inc
Idioma: Inglês

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MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy

Kojima, Kensuke ; Konopleva, Marina ; Samudio, Ismael J. ; Shikami, Masato ; Cabreira-Hansen, Maria ; McQueen, Teresa ; Ruvolo, Vivian ; Tsao, Twee ; Zeng, Zhihong ; Vassilev, Lyubomir T. ; Andreeff, Michael

Washington, DC: Elsevier Inc

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