title: 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.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Ismael J
authors.initials: IJ
authors.lastname: Samudio
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Seshagiri
authors.initials: S
authors.lastname: Duvvuri
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Watt
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Duncan
authors.initials: D
authors.lastname: Mak
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston TX.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Ascenta Therapeutics.
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston TX.
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston TX.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007211:Indoles; C482775:MDM4 protein, human; C543589:MI-63 compound; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2