Abstract 2502: p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells

Abstract

Abstract We previously showed that AZD1152-HQPA, the inhibitor of Aurora B kinase potently induced growth arrest and apoptosis of various types of human leukemia cells including MV4-11 acute myelogenous leukemia (AML) cells, although the molecular mechanisms by which this class of kinase inhibitors induces apoptosis remain to be fully elucidated. We have recently established the MV4-11 subline, designated as MV4-11 TP53 R248W, which possesses transcriptionally inactive R248W mutation in the TP53 gene. MV4-11 TP53 R248W cells were relatively resistant to AZD1152-HQPA-mediated growth arrest, as measured by MTT and clonogenic assays. AZD1152-HQPA (10-100 nM, 48 hrs) strikingly induced apoptosis of MV4-11 cells, as assessed by Annexin V binding, loss of mitochondrial outer membrane potential, and activation of caspase cascade, in parallel with up-regulation of p53 and its target molecules Bax and Noxa. Notably, AZD1152-HQPA (10-100 nM, 48 hrs) induced polyploidy rather than apoptosis in MV4-11 TP53 R248W cells. The polyploid cells were eventually eliminated via apoptosis at later time period (72-120 hrs) in association with up-regulation of p73. Taken together, p53 plays an important role in AZD1152-HQPA induced growth arrest and early-onset of apoptosis in AML cells. P73 may mediate the late-onset of apoptosis to eliminate the polyploid cells caused by the inhibitor of Aurora B kinase. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2502.