Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation.
OBJECTIVE
Arsenic trioxide decreases proliferation of acute myeloid leukemia (AML) cells, but its precise mechanism of action is unknown.


METHODS
We studied the effect of arsenic trioxide on patient samples and the AML cell line HEL, which, like leukemic blasts from 50% of AML cases, has constitutively activated signal transducer and activator of transcription (STAT) proteins.


RESULTS
Arsenic trioxide induced mitotic arrest starting at 24 hours and significant cell death at 48 hours. These events were preceded by an arsenic trioxide dose-dependent down-regulation of activated STAT proteins starting at 6 hours. We hypothesized that arsenic trioxide inhibits protein tyrosine kinases (PTK), which, among others, phosphorylate and activate STATs. We therefore studied arsenic trioxide effects on Janus kinases and on three oncogenic PTKs that are known to activate STATs [FLT3, ZNF198/fibroblast growth factor receptor 1 (FGFR1), and BCR/ABL]. Arsenic trioxide reduced STAT3 activation by Janus kinases, altered phosphorylation and electrophoretic mobility of ZNF198/fibroblast growth factor receptor 1, reduced kinase protein level, and decreased STAT3 protein phosphorylation. Arsenic trioxide also reduced the phosphorylation of BCR/ABL and FLT3 with corresponding decreased STAT5 phosphorylation.


CONCLUSIONS
These results suggest a selective activity of arsenic trioxide on PTKs and will assist in developing clinical trials in AML.
Wetzler
Meir
M
Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. meir.wetzler@roswellpark.org
Brady
Michael T
MT
Tracy
Erin
E
Li
Zhang-Rong
ZR
Donohue
Kathleen A
KA
O'Loughlin
Kieran L
KL
Cheng
Yijun
Y
Mortazavi
Amir
A
McDonald
Amy A
AA
Kunapuli
Padmaja
P
Wallace
Paul K
PK
Baer
Maria R
MR
Cowell
John K
JK
Baumann
Heinz
H
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; C117597:CEP43 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D010087:Oxides; D011518:Proto-Oncogene Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C111777:ZMYM2 protein, human; D011505:Protein-Tyrosine Kinases; D000077237:Arsenic Trioxide