title: Evaluation of apoptosis induction by concomitant inhibition of MEK, mTOR, and Bcl-2 in human acute myelogenous leukemia cells.
abstract: Aberrant activation of multiple signaling pathways is common in acute myelogenous leukemia (AML) cells, which can be linked to a poor prognosis for patients with this disease. Previous research with mTOR or MEK inhibitors revealed cytostatic, rather than cytotoxic, effects in in vitro and in vivo AML models. We evaluated the combination effect of the mTOR inhibitor AZD8055 and the MEK inhibitor selumetinib on human AML cell lines and primary AML samples. This combination demonstrated synergistic proapoptotic effects in AML cells with high basal activation of MEK and mTOR. We next incorporated the BH3 mimetic ABT-737 into this combination regimen to block Bcl-2, which further enhanced the apoptogenic effect of MEK/mTOR inhibition. The combination treatment also had a striking proapoptotic effect in CD33(+)/CD34(+) AML progenitor cells from primary AML samples with NRAS mutations. Mechanistically, upregulation of the proapoptotic protein Bim, accompanied by the downregulation of the antiapoptotic protein Mcl-1 (mainly via protein degradation), seemed to play critical roles in enhancing the combination drug effect. Furthermore, the modulation of survivin, Bax, Puma, and X-chromosome-linked inhibitor of apoptosis protein (XIAP) expression suggested a role for mitochondria-mediated apoptosis in the cytotoxicity of the drug combination. Consequently, the concomitant blockade of prosurvival MEK/mTOR signaling and the deactivation of Bcl-2 could provide a mechanism-based integrated therapeutic strategy for the eradication of AML cells.
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Liran
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Twee
authors.initials: T
authors.lastname: Tsao
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of.
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Schober
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guichard
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of Leukemia and mandreef@mdanderson.org mkonople@mdanderson.org.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Authors' Affiliations: Section of Molecular Hematology and Therapy; Departments of Leukemia and mandreef@mdanderson.org mkonople@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D020298:U937 Cells
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D009025:Morpholines; D019253:Proto-Oncogene Proteins c-bcl-2; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases
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