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,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.
d'Anglemont de Tassigny
Alexandra
A
INSERM, U841 Equipe 3, Créteil, F-94010, France.
Berdeaux
Alain
A
Souktani
Rachid
R
Henry
Patrick
P
Ghaleh
Bijan
B
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000517:prevention & control*; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006016:Glycolates / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000235:genetics; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D006016:Glycolates; D000081082:Phosphoinositide-3 Kinase Inhibitors; C015765:MK 473; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid