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.