Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells that is inhibited by iron supplementation.
Doxorubicin is an anthracycline antibiotic generally used in the treatment of solid tumors, but its use is limited by a severe cardiotoxicity, which has been related to the generation of oxygen- and nitrogen-derived free radicals. We have demonstrated that doxorubicin induces nitric oxide (NO) synthesis in the rat cardiac cells H9c2: the drug, after a 24-h incubation, evoked a dose-dependent increase of both NO synthase (NOS) activity in the cells and nitrite levels in the culture supernatant; the accumulation of nitrite (a stable derivative of NO) was prevented by different NOS inhibitors. The increase of NO production was associated with an increased expression of the inducible NOS isoform gene. These effects were significantly inhibited by the coincubation of doxorubicin with iron nitrilotriacetate, a compound that releases iron into the cells. Our results suggest that doxorubicin could induce NO generation in cardiac cells by modifying the iron homeostasis.
Aldieri
Elisabetta
E
Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, 10126, Italy.
Bergandi
Loredana
L
Riganti
Chiara
C
Costamagna
Costanzo
C
Bosia
Amalia
A
Ghigo
Dario
D
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015153:Blotting, Western; D002460:Cell Line; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D009573:Nitrites; D012313:RNA; D004317:Doxorubicin; D007501:Iron; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate