Change in TNF-alpha receptor expression is a relevant event in doxorubicin-induced H9c2 cardiomyocyte cell death.
Doxorubicin (Doxo) is a widely used anticancer drug given for the treatment of leukemias, lymphomas, and solid tumors. Despite its potent antitumor effects, the cardiotoxicity of this drug limits its clinical use. The biochemical mechanisms of Doxo-induced cardiotoxicity remain unclear. Doxo has been shown to induce apoptosis in cardiomyocytes that seems to be responsible, at least in part, for Doxo cardiotoxicity. In this study, we investigated tumor necrosis factor-alpha (TNF-alpha) receptor-mediated signaling to better understand the causes of Doxo-induced cardiotoxicity. Here, we report that Doxo is a potent inducer of apoptosis in both H9c2 cardiomyocytes and U2OS osteosarcoma tumor cells, with significant differences in terms of kinetics and caspase activation between the two cell lines. Interestingly, Doxo-induced apoptosis is accompanied by relevant changes in TNF-alpha receptor levels in H9c2 cardiomyocytes but not in U2OS cells. Moreover, treatment with exogenous TNF-alpha strongly potentiates the apoptotic effect of Doxo in H9c2 cardiomyocytes but not in U2OS cells. Our findings show that the function of TNF receptors I and II is affected by Doxo to ultimately modulate apoptosis and cell survival in H9c2 cardiomyocytes, reinforcing the recent evidence of the relevant role of TNF-alpha receptor-mediated signaling in cardiotoxicity induced by anthracyclines.
Chiosi
Emilio
E
Department of Biochemistry and Biophysics, Second University of Naples, Medical School, 80138 Naples, Italy.
Spina
Annamaria
A
Sorrentino
Annunziata
A
Romano
Maria
M
Sorvillo
Luca
L
Senatore
Giovanna
G
D'Auria
Raffaella
R
Abbruzzese
Alberto
A
Caraglia
Michele
M
Naviglio
Silvio
S
Illiano
Gennaro
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin