Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells.
Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2. AZ20 synergistically enhanced cytarabine-induced proliferation inhibition and apoptosis, abolished cytarabine-induced S and G2/M cell cycle arrest, and cooperated with cytarabine in inducing DNA replication stress and damage in AML cell lines. These key findings were confirmed with another ATR-selective inhibitor AZD6738. Therefore, the cooperative induction of DNA replication stress and damage by ATR inhibition and cytarabine, and the ability of ATR inhibition to abrogate the G2 cell cycle checkpoint both contributed to the synergistic induction of apoptosis and proliferation inhibition in AML cell lines. Synergistic antileukemic interactions between AZ20 and cytarabine were confirmed in primary AML patient samples. Our findings provide insight into the mechanism of action underlying the synergistic antileukemic activity of ATR inhibition in combination with cytarabine in AML.
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
Jun
J
Ma
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
Xinyu
X
Li
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
Yongwei
Y
Su
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.|Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
Jianyun
J
Zhao
Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA.
Daniel A
DA
Luedtke
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
Valeria
V
Epshteyn
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Holly
H
Edwards
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
Guan
G
Wang
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
Zhihong
Z
Wang
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
Roland
R
Chu
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
Jeffrey W
JW
Taub
Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, P. R. China.
Hai
H
Lin
Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, P. R. China.
Yue
Y
Wang
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Yubin
Y
Ge
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003561:Cytarabine / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology*; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D055815:Young Adult
C581009:4-(4-(3-methylmorpholin-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-yl)-1H-indole; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D009025:Morpholines; D011743:Pyrimidines; D003561:Cytarabine; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins