title: Change in TNF-alpha receptor expression is a relevant event in doxorubicin-induced H9c2 cardiomyocyte cell death.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Second University of Naples, Medical School, 80138 Naples, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Chiosi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Spina
authors.forename: Annunziata
authors.initials: A
authors.lastname: Sorrentino
authors.forename: Maria
authors.initials: M
authors.lastname: Romano
authors.forename: Luca
authors.initials: L
authors.lastname: Sorvillo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Senatore
authors.forename: Raffaella
authors.initials: R
authors.lastname: D'Auria
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Silvio
authors.initials: S
authors.lastname: Naviglio
authors.forename: Gennaro
authors.initials: G
authors.lastname: Illiano
mesh_terms: 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*
chemical_list: 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