α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs

Masafumi Kumazaki, Hitoshi Ando, Masafumi Kakei, Kentarou Ushijima, Yosuke Taniguchi, Masashi Yoshida, Shiho Yamato, Satoshi Washino, Taka Aki Koshimizu, Akio Fujimura

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Abstract

Clinical use of arsenic trioxide (As2O3), which can induce the remission of relapsed or refractory acute promyelocytic leukemia, is often limited because of its cardiotoxicity. Symptoms of cardiotoxicity include acute cardiac conduction disturbances, such as QT prolongation. The present study was undertaken to evaluate the effects of α-lipoic acid (LA) on acute As2O3-induced ECG abnormalities (QTc interval prolongation) in anesthetized guinea pigs. Intravenous injection of As 2O3 in guinea pigs caused QTc interval prolongation, which was significantly attenuated by co-treatment with LA (0.35, 3.5 and 35 mg/kg) in a dose-dependent manner. In isolated guinea pig cardiomyocytes, the decrease in IKs current induced by As2O3 (1 μM) was rapidly restored to the basal level by the addition of LA (10 μM). Consistent with this finding, the As2O3-induced QTc interval prolongation was also improved rapidly by post-treatment with LA in guinea pigs. Electrospray ionization time-of-flight mass spectrometry analysis detected an expected peak of arsenic-LA complex in vitro, indicating that LA and As 2O3 form a new compound in vivo. In addition, pre-treatment with a chelating agent, British anti-Lewisite (BAL, 3.5 or 35 mg/kg), also attenuated the As2O3-induced QTc interval prolongation. In this study, co- and post-treatments with LA and pre-treatment with BAL ameliorated As2O3-induced acute QT prolongation in anesthetized guinea pigs. Because LA and probably BAL may bind to As 2O3, these agents may exert protective effects through their chelating activity. Further studies are needed to determine whether LA is beneficial as a prophylactic or rescue agent for acute promyelocytic leukemia patients treated with As2O3.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalEuropean Journal of Pharmacology
Volume705
Issue number1-3
DOIs
Publication statusPublished - Apr 5 2013

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Thioctic Acid
Guinea Pigs
Dimercaprol
Acute Promyelocytic Leukemia
Therapeutics
arsenic trioxide
Chelating Agents
Cardiac Myocytes
Intravenous Injections
Mass Spectrometry
Electrocardiography

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs. / Kumazaki, Masafumi; Ando, Hitoshi; Kakei, Masafumi; Ushijima, Kentarou; Taniguchi, Yosuke; Yoshida, Masashi; Yamato, Shiho; Washino, Satoshi; Koshimizu, Taka Aki; Fujimura, Akio.

In: European Journal of Pharmacology, Vol. 705, No. 1-3, 05.04.2013, p. 1-10.

Research output: Contribution to journalArticle

Kumazaki, M, Ando, H, Kakei, M, Ushijima, K, Taniguchi, Y, Yoshida, M, Yamato, S, Washino, S, Koshimizu, TA & Fujimura, A 2013, 'α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs', European Journal of Pharmacology, vol. 705, no. 1-3, pp. 1-10. https://doi.org/10.1016/j.ejphar.2013.02.027
Kumazaki, Masafumi ; Ando, Hitoshi ; Kakei, Masafumi ; Ushijima, Kentarou ; Taniguchi, Yosuke ; Yoshida, Masashi ; Yamato, Shiho ; Washino, Satoshi ; Koshimizu, Taka Aki ; Fujimura, Akio. / α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs. In: European Journal of Pharmacology. 2013 ; Vol. 705, No. 1-3. pp. 1-10.
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AU - Taniguchi, Yosuke

AU - Yoshida, Masashi

AU - Yamato, Shiho

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AU - Koshimizu, Taka Aki

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AB - Clinical use of arsenic trioxide (As2O3), which can induce the remission of relapsed or refractory acute promyelocytic leukemia, is often limited because of its cardiotoxicity. Symptoms of cardiotoxicity include acute cardiac conduction disturbances, such as QT prolongation. The present study was undertaken to evaluate the effects of α-lipoic acid (LA) on acute As2O3-induced ECG abnormalities (QTc interval prolongation) in anesthetized guinea pigs. Intravenous injection of As 2O3 in guinea pigs caused QTc interval prolongation, which was significantly attenuated by co-treatment with LA (0.35, 3.5 and 35 mg/kg) in a dose-dependent manner. In isolated guinea pig cardiomyocytes, the decrease in IKs current induced by As2O3 (1 μM) was rapidly restored to the basal level by the addition of LA (10 μM). Consistent with this finding, the As2O3-induced QTc interval prolongation was also improved rapidly by post-treatment with LA in guinea pigs. Electrospray ionization time-of-flight mass spectrometry analysis detected an expected peak of arsenic-LA complex in vitro, indicating that LA and As 2O3 form a new compound in vivo. In addition, pre-treatment with a chelating agent, British anti-Lewisite (BAL, 3.5 or 35 mg/kg), also attenuated the As2O3-induced QTc interval prolongation. In this study, co- and post-treatments with LA and pre-treatment with BAL ameliorated As2O3-induced acute QT prolongation in anesthetized guinea pigs. Because LA and probably BAL may bind to As 2O3, these agents may exert protective effects through their chelating activity. Further studies are needed to determine whether LA is beneficial as a prophylactic or rescue agent for acute promyelocytic leukemia patients treated with As2O3.

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