Doxorubicin induces early lipid peroxidation associated with changes in glucose transport in cultured cardiomyocytes.
Doxorubicin (DOX) has not only chronic, but also acute toxic effects in the heart, ascribed to the generation of reactive oxygen species (ROS). Focusing on the DOX-induced early biochemical changes in rat cardiomyocytes, we demonstrated that lipid peroxidation is an early event, in fact conjugated diene production increased after 1-h DOX exposure, while cell damage, evaluated as lactate dehydrogenase (LDH) release, was observed only later, when at least one third of the cell antioxidant defences were consumed. Cell pre-treatment with alpha-tocopherol (TC) inhibited both conjugated diene production and LDH release. In cardiomyocytes, DOX treatment caused a maximal increase in glucose uptake at 1 h, demonstrating that glucose transport may represent an early target for DOX. At longer times, as the cell damage become significant, the glucose uptake stimulation diminished. Immunoblotting of glucose transporter isoform GLUT1 in membranes after 1-h DOX exposure revealed an increase in GLUT1 amount similar to the increase in transport activity; both effects were inhibited by alpha TC. Early lipid peroxidation evokes an adaptive response resulting in an increased glucose uptake, presumably to restore cellular energy. The regulation of nutrient transport mechanisms in cardiomyocytes may be considered an early event in the development of the cardiotoxic effects of the anthracycline.
Hrelia
Silvana
S
Department of Biochemistry G. Moruzzi, University of Bologna, Via Irnerio 48, I-40126 Bologna, Italy. hrelia@biocfarm.unibo.it
Fiorentini
Diana
D
Maraldi
Tullia
T
Angeloni
Cristina
C
Bordoni
Alessandra
A
Biagi
Pier Luigi
PL
Hakim
Gabriele
G
D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005947:Glucose / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D005947:Glucose