title: Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO-pegylated epirubicin.
abstract: The use of the anthracycline epirubicin (EPI) is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte and endothelial cell apoptosis. Nitric oxide (NO) increases the antitumoral activity of several chemotherapics, while it provides protection against apoptosis induced by oxidative stress both in endothelial cells and cardiomyocytes. The aim of the present study was to investigate whether the addition of an NO-releasing moiety to a pegylated derivative of EPI (p-EPI-NO) confers to the drug a different cytotoxic profile against tumoral and normal cells. The cytotoxic profile of the drugs was investigated in Caco-2 cell line, in embryonic rat heart-derived myoblasts (H9c2), in adult cardiomyocytes, and in endothelial cells (HUVEC). p-EPI-NO was more efficient than EPI in inducing Caco-2 cell apoptosis, while it spared HUVEC, H9c2 cells and adult cardiomyocytes from EPI-induced toxicity. Exposure of cells to p-EPI-NO resulted in a NO-mediated inhibition of cellular respiration followed by mitochondrial membrane depolarization and cell death in Caco-2 cells but not in HUVEC and H9c2 cells in which mitochondrial membrane polarization was maintained at the expense of glycolytically generated ATP. These findings indicate that addition of an NO-releasing moiety to p-EPI increases the anti-neoplastic activity of the drug, while it reduces its cytotoxicity against nonneoplastic cells.
authors.affiliation: Clinica di Gastroenterologia ed Epatologia, Department Of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Santucci
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.forename: Francesco
authors.initials: F
authors.lastname: Veronese
authors.forename: Antonella
authors.initials: A
authors.lastname: Zacheo
authors.forename: Antonia
authors.initials: A
authors.lastname: Germani
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000378:metabolism; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010101:Oxygen Consumption; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; C510090:nitric oxide-pegylated epirubicin; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D015251:Epirubicin; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV