Journal
CELL CYCLE
Volume 5, Issue 23, Pages 2778-2786Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.5.23.3520
Keywords
AML; apoptosis; nutlin-3a; ABT-737; Bcl-2; p53
Categories
Funding
- NCI NIH HHS [P01 CA55164, P01 CA49639, CA16672] Funding Source: Medline
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Disruption of Mdm2-p53 interaction activates p53 signaling, disrupts the balance of antiapoptotic and proapoptotic Bcl-2 family proteins and induces apoptosis in acute myeloid leukemia (AML). Overexpression of Bcl-2 may inhibit this effect. Thus, functional inactivation of antiapoptotic Bcl-2 proteins may enhance apoptogenic effects of Mdm2 inhibition. We here investigate the potential therapeutic utility of combined targeting of Mdm2 by Nutlin-3a and Bcl-2 by ABT-737, recently developed inhibitors of protein-protein interactions. Nutlin-3a and ABT-737 induced Bax conformational change and mitochondrial apoptosis in AML cells in a strikingly synergistic fashion. Nutlin-3a induced 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.
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