A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives.
Fluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrations of 400 μM and 4 μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity. Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect.
Section of Occupational Medicine, Department of Experimental Medicine Second University of Naples, Naples, Italy. Electronic address: monicalamberti@libero.it.
Monica
M
Lamberti
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Stefania
S
Porto
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Silvia
S
Zappavigna
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Erasmo
E
Addeo
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Monica
M
Marra
Section of Occupational Medicine, Department of Experimental Medicine Second University of Naples, Naples, Italy.
Nadia
N
Miraglia
Section of Occupational Medicine, Department of Experimental Medicine Second University of Naples, Naples, Italy.
Nicola
N
Sannolo
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Daniela
D
Vanacore
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Paola
P
Stiuso
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Michele
M
Caraglia
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005472:Fluorouracil / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D016273:Occupational Exposure / Q000009:adverse effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000963:Antimetabolites; D016166:Free Radical Scavengers; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D002955:Leucovorin; D005472:Fluorouracil
5-Fluorouracil; Cardiotoxicity; Occupational health; Rat cardiocytes model