Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes

• Published in: Fundamental & clinical pharmacology Vol. 18; no. 5; pp. 531 - 538
• Main Authors: D'Anglemont De Tassigny, Alexandra, Souktani, Rachid, Henry, Patrick, Ghaleh, Bijan, Berdeaux, Alain
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2004; Blackwell; Wiley
• Subjects: Ageing, cell death; Animals; Annexin A5 - metabolism; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell membranes. Ionic channels. Membrane pores; Cell physiology; Cell Size - drug effects; Cell structures and functions; cell volume; Cells, Cultured; chloride channel; Chloride Channels - physiology; Doxorubicin - pharmacology; Fundamental and applied biological sciences. Psychology; Heart Ventricles - cytology; Life Sciences; Male; Molecular and cellular biology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Osmotic Pressure; Patch-Clamp Techniques; Rabbits; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Time Factors; Antineoplastic agent; DNA topoisomerase (ATP-hydrolysing); Enzyme; Enzyme inhibitor; Ionic channel; Doxorubicin; Antibiotic; Isomerases; Cell death; chloride channel; Chlorides; Anthracyclins; Cell volume; Apoptosis
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2004.00273.x

Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume‐sensitive chloride channels (ICl,vol) are known to play a key role in the regulation of cell volume, this study investigated the role of ICl,vol and AVD in doxorubicin‐induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 μm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase‐3 activity. Doxorubicin also induced the activation of a current characterized as ICl,vol on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin‐induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the ICl,vol inhibitors 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) (0.1 mm) or indanyloxyacetic acid 94 (IAA‐94) (10 μm). The crucial role of ICl,vol during AVD and apoptosis was confirmed using C2‐ceramide, another pro‐apoptotic compound. These results demonstrate that activation of ICl,vol plays a major role in the mechanism leading to cell shrinkage and apoptosis‐induced AVD by agents such as doxorubicin or C2‐ceramide in adult cardiomyocytes.