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Journal of Environmental Pathology, Toxicology and Oncology
IF: 1.15 5-Year IF: 1.4 SJR: 0.519 SNIP: 0.613 CiteScore™: 1.61

ISSN Print: 0731-8898
ISSN Online: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvironPatholToxicolOncol.v28.i3.60
pages 241-252

Evaluation of Adverse Cardiac Effects Induced by Arsenic Trioxide, a Potent Anti-APL Drug

K. G. Raghu
Pharmacology Division,Central Drug Research Institute, Lucknow,UP; Biochemistry and Cell Culture Laboratory,Agroprocessing&Natural Products Division,National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram,Kerala,India
Govind Kumar Yadav
Pharmacology Division, Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh (UP), India, 226001
Richa Singh
Pharmacology Division, Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh (UP), India, 226001
A. Prathapan
Biochemistry and Cell Culture Laboratory, Agroprocessing & Natural Products Division, National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019
Sharad Sharma
Toxicology Division, Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh (UP), India, 226001
Smrati Bhadauria
Toxicology Division, Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh (UP), India, 226001

ABSTRACT

Arsenic trioxide (ATO/As2O3) is a promising drug for patients with a relapse of acute promyelocytic leukemia (APL); however, it frequently causes fatal arrhythmias. This study aims to investigate the various cellular and molecular mechanisms of adverse cardiac effects and the electrophysi-ological alterations caused by As2O3. We show the dose-dependent effect of ATO (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 μm) on electrically driven cardiac action potential from the papillary muscle of the guinea pig. ATO causes a significant prolongation of action potential duration (APD) at various levels of repolarization, conduction delay, and increased triangulation, which is a novel marker for the proarrhythmic potential of a compound. Electrolyte imbalance (hypomagnesemia and hypokalemia) has also been found to cause amplification of ATO toxicity. Since ion channels play a very important role in the generation of cardiac action potential, we used various ion channel modulators such as choline, minoxidil, nifedipine, and verapamil to determine whether these agents could antagonize electrophysiological alterations caused by ATO. In in vivo experiments, ATO administration to animals for 10 days caused myocardial disorganization, interstitial edema and infiltration of inflammatory cells in the heart. Efforts were also made to screen the efficacy of vitamin C against ATO toxicity. ATO also caused a significant increase in the activity of certain clinically relevant enzymes for cardiac function and antioxidant mechanisms—such as serum creatine kinase isoenzyme, lactate dehydrogenase, glutathione peroxidase and reduced glutathione. In conclusion, ATO causes significant adverse cardiac effects and we suggest that cardiac function to be monitored during treatment with ATO. Our results also indicate that the status of the body's main electrolyte content (such as magnesium and potassium) is also an influencing factor on the magnitude of toxicity of arsenic trioxide.


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