title: Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol.
abstract: The PI3K/Akt signaling pathway is constitutively activated in various leukemias. In the present study, the topoisomerase inhibitor, 3EZ, 20Ac-ingenol, was more effective in inhibiting the growth of BALL-1 cells than that of normal lymphocyte cells. ATM/ATR protein levels were increased, PTEN protein was upregulated, and p-Akt protein was downregulated at early time points after treatment with 3EZ, 20Ac-ingenol. In further experiments, p53 protein expression was increased, and H2AX phosphorylation and p21 protein expression were induced after treatment with 3EZ, 20Ac-ingenol. Moreover, the activation of caspase 3 followed decrease in the Bcl-2/Bax ratio after treatment with 3EZ, 20Ac-ingenol, and accumulation of sub-G1 phase cells was observed in flow cytometry analyses. These data suggest that 3EZ, 20Ac-ingenol-induced DNA damage downregulates p-Akt and upregulates ATR leading to cell cycle arrest and increased apoptosis in BALL-1 cells.
authors.affiliation: Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan. Electronic address: miyata@chs.nihon-u.ac.jp.
authors.forename: Shohei
authors.initials: S
authors.lastname: Miyata
authors.affiliation: Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Tojima
authors.affiliation: School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Matsuzaki
authors.affiliation: School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kitanaka
authors.affiliation: Department of Integrated Sciences in Physics and Biology, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sawada
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia; D051059:PTEN Phosphohydrolase / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; C468783:H2AX protein, human; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; D059003:Topoisomerase Inhibitors; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053148:Caspase 3
keywords: ATM/ATR; Apoptosis; Inhibition of proliferation; PTEN/Akt; Topo catalytic inhibitor; p53