The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2

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,I-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,I-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,I-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,I-vol inhibitors were abolished by previous inhibition of PI(3)kinase, Akt and Erk 1/2. Thus, I-Cl,I-vol inhibitors prevent doxorubicin-induced apoptosis and subsequent contractile dysfunction through PI(3)kinase/Akt and Erk 1/2. Inhibition of I-Cl,I-vol may represent a new pharmacological strategy for developing cytoprotective drugs against apoptotic cell death and contractile dysfunction. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.