TY - JOUR
T1 - Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes
T2 - Role for heme oxygenase-1 down-modulation
AU - Bernuzzi, Francesca
AU - Recalcati, Stefania
AU - Alberghini, Alessandra
AU - Cairo, Gaetano
PY - 2009/1/15
Y1 - 2009/1/15
N2 - Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of doxorubicin (DOX) as an anti-tumoral drug, but the mechanism of DOX-mediated apoptosis remains unclear. We examined the interplay between oxidative stress and cell death in cardiac-derived H9c2 myocytes exposed to DOX doses in the range of the plasma levels found in patients undergoing chemotherapy. A low DOX concentration (0.25 μM) induced apoptosis, whereas the cells treated with the high dose of 2 μM also showed necrosis. The production of reactive oxygen species (ROS) and induction of oxidative stress markers was increased in the cells treated with 2 μM DOX but not in those treated with the low dose. Surprisingly, heme oxygenase (HO-1) expression was down-modulated in the cells exposed to 0.25 μM DOX, and its Bach 1 transcriptional repressor was induced. In line with the role of HO-1 as an anti-apoptotic protein, inhibiting HO-1 activity with SnPPIX was sufficient to induce apoptosis and increased DOX-mediated apoptosis, whereas hemin-induced HO-1 activation prevented DOX-mediated apoptotic cell death. In brief, our findings do not support the hypothesis that oxidative stress plays a role in the apoptotic cell death occurring in cardiomyocytes exposed to low concentrations of DOX, but suggest that DOX may facilitate the apoptosis of cardiomyocytes by inhibiting the anti-apoptotic HO-1.
AB - Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of doxorubicin (DOX) as an anti-tumoral drug, but the mechanism of DOX-mediated apoptosis remains unclear. We examined the interplay between oxidative stress and cell death in cardiac-derived H9c2 myocytes exposed to DOX doses in the range of the plasma levels found in patients undergoing chemotherapy. A low DOX concentration (0.25 μM) induced apoptosis, whereas the cells treated with the high dose of 2 μM also showed necrosis. The production of reactive oxygen species (ROS) and induction of oxidative stress markers was increased in the cells treated with 2 μM DOX but not in those treated with the low dose. Surprisingly, heme oxygenase (HO-1) expression was down-modulated in the cells exposed to 0.25 μM DOX, and its Bach 1 transcriptional repressor was induced. In line with the role of HO-1 as an anti-apoptotic protein, inhibiting HO-1 activity with SnPPIX was sufficient to induce apoptosis and increased DOX-mediated apoptosis, whereas hemin-induced HO-1 activation prevented DOX-mediated apoptotic cell death. In brief, our findings do not support the hypothesis that oxidative stress plays a role in the apoptotic cell death occurring in cardiomyocytes exposed to low concentrations of DOX, but suggest that DOX may facilitate the apoptosis of cardiomyocytes by inhibiting the anti-apoptotic HO-1.
KW - Anthracyclines
KW - Cell death
KW - Chemotherapy
KW - Heart
KW - Oxidative stress
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UR - http://www.scopus.com/inward/citedby.url?scp=57349125695&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2008.09.012
DO - 10.1016/j.cbi.2008.09.012
M3 - Article
C2 - 18845130
AN - SCOPUS:57349125695
VL - 177
SP - 12
EP - 20
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
SN - 0009-2797
IS - 1
ER -