Activation of P53 Signaling by MI-63 Induces Apoptosis in Acute Myeloid Leukemia Cells

Overview

Journal Leuk Lymphoma

Specialties Hematology
Oncology

Date 2010 Apr 29

PMID 20423286

Citations 7

Authors

Ismael J Samudio

Seshagiri Duvvuri

Karen Clise-Dwyer

Julie C Watt

Duncan Mak

Hagop Kantarjian

Dajun Yang

Vivian Ruvolo

Gautam Borthakur

Affiliations

Soon will be listed here.

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.

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