Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts.
OBJECTIVE
Doxorubicin (DOX) is a widely prescribed chemotherapeutic. The hypothesis for the present study is that DOX-induced myocyte apoptosis involves mitochondrial dysfunction that is a consequence of nuclear DOX effects.


METHODS
H9c2 myoblasts were incubated with 0, 0.5 and 1 muM DOX and nuclear and mitochondrial alterations were determined.


RESULTS
Doxorubicin accumulation in the nucleus was detected after 3 h treatment, followed by an increase in p53 and a decrease in mitochondrial membrane potential. Apoptotic markers, such as caspase activation and chromatin condensation were detected after 24 h of DOX treatment. Bax and p53 translocation to mitochondria as well as the formation of Bax clusters in the cytosol were observed. Importantly, pifithrin-alpha, a p53 inhibitor, protected against DOX-induced mitochondrial depolarization, caspase activation and cell death.


CONCLUSIONS
Mitochondrial dysfunction in H9c2 myoblasts treated with DOX is a consequence of nuclear p53 activation rather than a direct effect of the drug on mitochondria.
Sardão
Vilma A
VA
Department of Zoology, Center for Neurosciences and Cellular Biology, University of Coimbra, Coimbra, Portugal. vimarisa@ci.uc.pt
Oliveira
Paulo J
PJ
Holy
Jon
J
Oliveira
Catarina R
CR
Wallace
Kendall B
KB
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation; D004261:DNA Replication / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D018613:Microscopy, Confocal; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin