title: AML sensitivity to YM155 is modulated through AKT and Mcl-1.
abstract: HL60 and U937 (acute myeloid leukemia (AML) cell lines) were assessed for sensitivity to YM155, and found to have distinct sensitive and resistant phenotypes, respectively. In HL60 cells, YM155 inhibition of growth proliferation was due to apoptosis which was measured by annexin V/PI staining. YM155 induced apoptosis through activation of intrinsic and extrinsic pathways that also culminated in caspase-3 activity and PARP cleavage. YM155 sensitivity was partially associated with this compound's ability to down-regulate survivin transcription since this was more pronounced in the HL60 cell line. However, marked differences were also observed in XIAP, Bcl-2, and Mcl-1L, and Mcl-1s. Furthermore, YM155 treatment completely inhibited production of total Akt protein in HL60, but not U937 cells. Importantly, Akt activity (pAkt-Ser473) levels were maintained in YM155 treated U937 cells which may help stabilize other anti-apoptotic proteins. Combination treatments with an Akt inhibitor, MK-2206, reduced levels of pAkt-Ser473 in U937 cells and synergistically sensitized them to YM155 cytotoxicity. Collectively our results indicate that Akt signaling may be an important factor mediating YM155 response in AML, and combinatorial therapies with Akt inhibitors could improve treatment efficacy in YM155-resistant cells.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Rosalia
authors.initials: R
authors.lastname: de Necochea-Campion
authors.affiliation: Center for Health Disparities & Molecular Medicine, Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Diaz Osterman
authors.affiliation: Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Heng-Wei
authors.initials: HW
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Saied
authors.initials: S
authors.lastname: Mirshahidi
authors.affiliation: Center for Health Disparities & Molecular Medicine, Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, CA 92350, USA. Electronic address: nwall@llu.edu.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wall
authors.affiliation: Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA. Electronic address: cschen@llu.edu.
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D000077022:Survivin; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; C523798:sepantronium
keywords: AML; Akt; Bcl-2; Mcl-1; XIAP; YM155