Doxorubicin- and daunorubicin-induced energy deprivation and nucleotide degradation in isolated cardiomyocytes.
Cytotoxic mechanisms of the antitumor agents daunorubicin and doxorubicin were elucidated in isolated cardiomyocytes from adult rats. Incubation with daunorubicin resulted in a concentration-dependent loss of cell viability and changes of the cell structure. Only the highest concentration of doxorubicin (1 mM) caused similar effects. Doxorubicin was found to stimulate oxygen consumption by cardiomyocytes (about 20%), while the opposite effect was observed after daunorubicin treatment. A rapid decrease of the mitochondrial ATP content (more than 40%) and elevation of the cytosolic ADP level (doxorubicin 2-fold and daunorubicin 6-fold) was followed by increased release of adenosine and inosine to the surrounding medium. When myocytes were exposed to an anthracycline concentration lower than plasma levels measured clinically (0.15 microM), doxorubicin and daunorubicin significantly decreased the intracellular ADP and NAD levels. Isolated cardiomyocytes were found to be able to form daunorubicinol from daunorubicin. In contrast, no conversion of doxorubicin was detected in our experiments. In conclusion, our data demonstrate that decreased ATP production and increased nucleoside formation are major events in the toxicity induced by daunorubicin and doxorubicin in isolated cardiomyocytes. The results also suggest that the toxic effects may be caused by separate mechanisms.
Vidal
R F
RF
Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
Eksborg
S
S
Sundberg
M
M
Carlberg
M
M
Elfsson
B
B
Andersson
B S
BS
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002469:Cell Separation; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000166:cytology*; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D009249:NADP; D000244:Adenosine Diphosphate; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D003630:Daunorubicin