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 (ICl,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 ICl,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 ICl,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 ICl,vol inhibitors were abolished by previous inhibition of PI3kinase, Akt and Erk 1/2. Thus, ICl,vol inhibitors prevent doxorubicin-induced apoptosis and subsequent contractile dysfunction through PI3kinase/Akt and Erk 1/2. Inhibition of ICl,vol may represent a new pharmacological strategy for developing cytoprotective drugs against apoptotic cell death and contractile dysfunction.