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

Shohei Miyata; Yasuaki Fukuda; Haruka Tojima; Keiichi Matsuzaki; Susumu Kitanaka; Hiroshi Sawada

doi:10.1016/j.leukres.2015.06.006

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

Leuk Res. 2015 Sep;39(9):927-32. doi: 10.1016/j.leukres.2015.06.006. Epub 2015 Jun 14.

Authors

Shohei Miyata¹, Yasuaki Fukuda², Haruka Tojima², Keiichi Matsuzaki³, Susumu Kitanaka³, Hiroshi Sawada⁴

Affiliations

¹ Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan. Electronic address: miyata@chs.nihon-u.ac.jp.
² Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan.
³ School of Pharmacy, Nihon University, Chiba, Japan.
⁴ Department of Integrated Sciences in Physics and Biology, College of Humanities and Sciences, Nihon University, Tokyo, Japan.

PMID: 26194899
DOI: 10.1016/j.leukres.2015.06.006

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.

Keywords: ATM/ATR; Apoptosis; Inhibition of proliferation; PTEN/Akt; Topo catalytic inhibitor; p53.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism
Caspase 3 / genetics
Caspase 3 / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Diterpenes / pharmacology*
Gene Expression Regulation, Leukemic*
Histones / genetics
Histones / metabolism
Humans
Leukemia
PTEN Phosphohydrolase / agonists*
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Signal Transduction
Topoisomerase Inhibitors / pharmacology*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Cyclin-Dependent Kinase Inhibitor p21
Diterpenes
H2AX protein, human
Histones
Proto-Oncogene Proteins c-bcl-2
Topoisomerase Inhibitors
Tumor Suppressor Protein p53
Phosphatidylinositol 3-Kinases
ATM protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human
Caspase 3