Genistein ameliorates adverse cardiac effects induced by arsenic trioxide through preventing cardiomyocytes apoptosis.
OBJECTIVE
Arsenic trioxide (As2O3) is a highly effective agent for treatment of acute promyelocytic leukemia (APL). However, consecutively administered As2O3 induces serious adverse cardiac effects, including long QT syndrome (LQTs) and even sudden cardiac death. Previous studies have shown that genistein (Gen) exerts anti-oxidant, anti-inflammatory, and anti-apoptotic effects. The present study aimed to explore the potential protective effects of Gen on As2O3-induced adverse cardiac effects, and to elucidate the underlying molecular mechanisms.


METHODS
A rat model of As2O3-induced QT prolongation was generated by intravenous injection with As2O3. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca(2+)]i) and mitochondrial membrane potential (Δψm) were measured by confocal microscopy, and cardiomyocytes apoptosis were assessed by TUNEL assay. Western blot was applied to determine protein levels.


RESULTS
We found for the first time that treatment with Gen significantly reversed LQTs and dose-dependently improved As2O3-induced impairment of cardiac function. As2O3 elevated [Ca(2+)]i and Gen mitigated this effect. Meanwhile, Gen significantly reversed As2O3-mediated cardiomyocytes apoptosis. Furthermore, Gen dose-dependently inhibited the phosphorylated JNK and p38-MAPK (pp38-MAPK), and blocked Δψm collapse, and further decreased cleaved caspase-3.


CONCLUSIONS
Gen protects against the adverse cardiac effects of As2O3 partly by mitigating cardiomyocytes apoptosis induced by As2O3 through attenuating intracellular calcium overload and downregulating protein expression of p-JNK and pp38-MAPK to ameliorate the damage of Δψm leading to suppression of caspase-3 activation. Gen might be used as an adjunction therapy in APL patients receiving As2O3 treatment to avoid, at least to minimize, the adverse cardiac effects of As2O3.
Institute of Clinical Pharmacy, the Second Affiliated Hospital, Harbin Medical University, Harbin, China.
Yuhua
Y
Fan
Chen
C
Wang
Yong
Y
Zhang
Pengzhou
P
Hang
Yan
Y
Liu
Zhenwei
Z
Pan
Ning
N
Wang
Zhimin
Z
Du
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004562:Electrocardiography; D019833:Genistein / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016588:Anticarcinogenic Agents; D001152:Arsenicals; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D010087:Oxides; D019833:Genistein; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077237:Arsenic Trioxide; D002118:Calcium