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d'Anglemont de Tassigny A, Berdeaux A, Souktani R, Henry P, Ghaleh B: The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2. Eur J Heart Fail. 2008 Jan;10(1):39-46.
Contractile dysfunction and cardiomyopathies secondary to apoptotic cell death are limiting factors for treating cancer with doxorubicin. Inhibition of volume-sensitive chloride currents (I (Cl,vol)) has been reported to blunt doxorubicin-induced apoptosis in cardiomyocytes. To investigate cellular contractility during acute induction of apoptosis by doxorubicin and to determine whether I (Cl,vol) inhibitors are able to prevent the subsequent contractile dysfunction, electrically paced ventricular myocytes freshly isolated from adult rabbits were acutely exposed to doxorubicin in the presence and absence of I (Cl,vol) inhibitors IAA-94 or DIDS. Doxorubicin induced increases in both annexin V labelling and caspase-3 activity and decreases in cell volume. Alteration in cardiac contractility was observed after doxorubicin exposure. Both IAA-94 and DIDS abolished the doxorubicin-induced decreases in peak shortening and cell volume as well as the increases in caspase-3 activity and annexin V labelling. These protective effects of I (Cl,vol) inhibitors were abolished by previous inhibition of PI (3) kinase, Akt and Erk 1/2. Thus, I (Cl,vol) inhibitors prevent doxorubicin-induced apoptosis and subsequent contractile dysfunction through PI (3) kinase/Akt and Erk 1/2. Inhibition of I (Cl,vol) may represent a new pharmacological strategy for developing cytoprotective drugs against apoptotic cell death and contractile dysfunction. |
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