Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

• Published in: Cell cycle (Georgetown, Tex.) Vol. 5; no. 23; pp. 2778 - 2786
• Main Authors: Kojima, Kensuke, Konopleva, Marina, Samudio, Ismael J, Schober, Wendy D, Bornmann, William, Andreeff, Michael
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-12-2006
• Subjects: Animals; Annexin A5 - metabolism; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Binding; Biology; Bioscience; Biphenyl Compounds - pharmacology; Calcium; Cancer; Cell; Cell Line, Tumor; Cycle; Drug Resistance, Neoplasm; G1 Phase - drug effects; G2 Phase - drug effects; Humans; Imidazoles - pharmacology; Landes; Leukemia, Myeloid, Acute - pathology; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitosis - drug effects; Mutant Proteins - metabolism; Nitrophenols - pharmacology; Organogenesis; Phosphorylation - drug effects; Piperazines - pharmacology; Protein Conformation - drug effects; Proteins; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; S Phase - drug effects; Sulfonamides - pharmacology; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.5.23.3520

Disruption of Mdm2-p53 interaction activates p53 signaling, disrupts the balance ofantiapoptotic and proapoptotic Bcl-2 family proteins and induces apoptosis in acutemyeloid leukemia (AML). Overexpression of Bcl-2 may inhibit this effect. Thus,functional inactivation of antiapoptotic Bcl-2 proteins may enhance apoptogenic effects ofMdm2 inhibition. We here investigate the potential therapeutic utility of combinedtargeting of Mdm2 by Nutlin-3a and Bcl-2 by ABT-737, recently developed inhibitors ofprotein-protein interactions. Nutlin-3a and ABT-737 induced Bax conformational changeand mitochondrial apoptosis in AML cells in a strikingly synergistic fashion. Nutlin-3ainduced p53-mediated apoptosis predominantly in S and G
2
/M cells, while cells in G
1
were protected through induction of p21. In contrast, ABT-737 induced apoptosis predominantly in G
1
, the cell cycle phase with the lowest Bcl-2 protein levels and Bcl-2/Bax ratios. In addition, Bcl-2 phosphorylation on Ser
70
was absent in G
1
but detectable in G
2
/M, thus lower Bcl-2 levels and absence of Bcl-2 phosphorylation appeared to facilitate ABT-737-induced apoptosis of G
1
cells. The complementary effects of Nutlin-3a and ABT-737 in different cell cycle phases could, in part, account for their synergistic activity. Our data suggest that combined targeting of Mdm2 and Bcl-2 proteins could offer considerable therapeutic promise in AML.