Abstract
Background/Aims: Arsenic trioxide (As<sub>2</sub>O<sub>3</sub>) is a highly effective agent for treatment of acute promyelocytic leukemia (APL). However, consecutively administered As<sub>2</sub>O<sub>3</sub> 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 As<sub>2</sub>O<sub>3</sub>-induced adverse cardiac effects, and to elucidate the underlying molecular mechanisms. Methods: A rat model of As<sub>2</sub>O<sub>3</sub>-induced QT prolongation was generated by intravenous injection with As<sub>2</sub>O<sub>3</sub>. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>) 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 As<sub>2</sub>O<sub>3</sub>-induced impairment of cardiac function. As<sub>2</sub>O<sub>3</sub> elevated [Ca<sup>2+</sup>]<sub>i</sub> and Gen mitigated this effect. Meanwhile, Gen significantly reversed As<sub>2</sub>O<sub>3</sub>-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. Conclusion: Gen protects against the adverse cardiac effects of As<sub>2</sub>O<sub>3</sub> partly by mitigating cardiomyocytes apoptosis induced by As<sub>2</sub>O<sub>3</sub> 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 As<sub>2</sub>O<sub>3</sub> treatment to avoid, at least to minimize, the adverse cardiac effects of As<sub>2</sub>O<sub>3</sub>.
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