Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks)

Autor: Ducroq, Joffrey, Moha Ou Maati, H., Guilbot, S., Dilly, S., Laemmel, E., Pons-Himbert, C., Faivre, J. F., Bois, P., Stücker, O., Le Grand, M.
Přispěvatelé: PHYSIOSTIM, Entreprise physiostim, Institut de physiologie et biologie cellulaires (IPBC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), APT Pharmaceuticals, Laboratoire d'Etude de la Microcirculation, Centre National de la Recherche Scientifique (CNRS), CEROM, Entreprise CEROM
Jazyk: angličtina
Rok vydání: 2010
Předmět:
MESH: Delayed Rectifier Potassium Channels
Themed Section
Guinea Pigs
Moxifloxacin
Drug Evaluation
Preclinical
MESH: Ether-A-Go-Go Potassium Channels
In Vitro Techniques
Cell Line
MESH: Guinea Pigs
MESH: Dose-Response Relationship
Drug
Inhibitory Concentration 50
MESH: Doxorubicin
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication
MESH: Razoxane
Animals
Humans
MESH: Animals
MESH: Antibiotics
Antineoplastic
MESH: Inhibitory Concentration 50
Aza Compounds
Antibiotics
Antineoplastic
MESH: Humans
Dose-Response Relationship
Drug
MESH: Long QT Syndrome
Cardiovascular Agents
Ether-A-Go-Go Potassium Channels
MESH: Cell Line
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biophysics
Long QT Syndrome
Doxorubicin
MESH: Aza Compounds
Quinolines
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
MESH: Drug Evaluation
Preclinical
MESH: Cardiovascular Agents
Razoxane
MESH: Quinolines
Delayed Rectifier Potassium Channels
Fluoroquinolones
Zdroj: British Journal of Pharmacology
British Journal of Pharmacology, Wiley, 2010, 159 (1), pp.93-101. ⟨10.1111/j.1476-5381.2009.00371.x⟩
ISSN: 0007-1188
1476-5381
DOI: 10.1111/j.1476-5381.2009.00371.x⟩
Popis: Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin.The effects of moxifloxacin (100 microM) and doxorubicin (30 microM), with or without dexrazoxane (from 3 to 30 microM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on I(Kr) (rapid component of the delayed rectifier current) and I(Ks) (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells.Moxifloxacin (100 microM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 microM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited I(Ks) (IC(50): 4.78 microM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of I(Ks).Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective I(Ks) blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting I(Ks) in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes.
Databáze: OpenAIRE
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