Activation of p53 signaling by MI-63 induces apoptosis in acute myeloid leukemia cells

Abstract

Non-mutational inactivation of p53 is frequent in acute myeloid leukemia (AML) via overexpression of MDM2. We report that treatment with MI-63, a novel inhibitor of MDM2, activates p53 signaling to induce apoptosis in AML cell lines and primary samples. Cell lines naturally devoid of p53 or expressing shRNA targeting p53 are refractory to apoptosis induction by MI-63, indicating that the effects of MI-63 require p53 expression. MI-63 induced G1 phase arrest and increased p21 expression. MI-63 induced pronounced apoptosis in all primary AML samples tested, and most important, was effective in inducing cell death of leukemia ‘stem’ cells. In addition, MI-63 showed synergy with both doxorubicin and AraC. Interestingly, treatment with MI-63 also led to a reduction in levels of MDM4 protein, a repressor of p53 mediated transcription, in AML cells. Our results warrant investigation of MI-63 or its analogs as anti-leukemic agents, alone or in combination with traditional chemotherapeutic agents.

Keywords:

• MDM2
• MI-63
• acute myelogenoid leukemia
• p53

Acknowledgements

MI-63 and its inactive enantiomer MI-61 were kindly provided by: Ascenta Therapeutics, 101 Lindenwood Drive, Suite 405, Malvern, PA 19355.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.