The expression of p38, ERK1 and Bax proteins has increased during the treatment of newly diagnosed acute promyelocytic leukemia with arsenic trioxide.
BACKGROUND
Promising reports exist regarding the use of arsenic trioxide (ATO) as first-line treatment in acute promyelocytic leukemia (APL). Although the in vitro effect of ATO is extensively studied, the in vivo mechanism(s) of ATO action is mostly unknown.


METHODS
Newly diagnosed APL patients were involved and received ATO (0.15 mg.kg/day) for 28 days as induction followed by consolidation therapy. Bone marrow (BM) aspirates were obtained on days 0, 14 and 28 of treatment for further molecular studies. Clinical findings and white blood cell counts were recorded as well.


RESULTS
Complete remission was observed in 17 (85%) patients with the median duration of 28 days (18-38) and cumulative dosage of median 280 mg (180-350). Hyperleukocytosis and APL differentiation syndrome (63%), gastrointestinal disorders (30%), liver enzyme elevation and night sweating (50%) were the most prevalent side-effects. The expression of Bax, ERK1 and p38 proteins and caspase-3 activity increased significantly in promyelocytes of BM aspirates at days 14 and 28 of induction therapy.


CONCLUSIONS
These findings point toward the role of p38 and Bax in the induction of apoptosis, which was confirmed by increase in caspase-3 activity. However, the increase in ERK1 expression with regard to leukocytosis could translate to a proliferative/differentiation effect.
Mandegary
A
A
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman.
Hosseini
R
R
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran.
Ghaffari
S H
SH
Hematology, Oncology and BMT Research Center, Tehran University of Medical Sciences, Shariati Hospital, Tehran.
Alimoghaddam
K
K
Hematology, Oncology and BMT Research Center, Tehran University of Medical Sciences, Shariati Hospital, Tehran; Department of Molecular Medicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran.
Rostami
S
S
Hematology, Oncology and BMT Research Center, Tehran University of Medical Sciences, Shariati Hospital, Tehran.
Ghavamzadeh
A
A
Hematology, Oncology and BMT Research Center, Tehran University of Medical Sciences, Shariati Hospital, Tehran.
Ghahremani
M H
MH
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran; Department of Molecular Medicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: mhghahremani@tums.ac.ir.
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D010087:Oxides / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001152:Arsenicals; C494826:BAX protein, human; D010087:Oxides; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide