tFluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The pos-sible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remaina puzzle to solve for investigators. In the present study, we study what cell death pathways and whatdoses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on ratcardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitiveto 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrationsof 400 M and 4 M on H9c2 and HT-29, respectively. Moreover, we have found that the addition ofLevofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibitioninduced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thio-barbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase ofthe oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by theaddition of LF, a biochemical modulator of 5-FU activity.Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to theinduction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. Thestrategies based upon the use of scavengers could be used in order to prevent this effect.
A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives.
LAMBERTI, Monica;Zappavigna, S;MIRAGLIA, Nadia;SANNOLO, Nicola;STIUSO, Paola;CARAGLIA, Michele
2014
Abstract
tFluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The pos-sible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remaina puzzle to solve for investigators. In the present study, we study what cell death pathways and whatdoses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on ratcardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitiveto 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrationsof 400 M and 4 M on H9c2 and HT-29, respectively. Moreover, we have found that the addition ofLevofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibitioninduced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thio-barbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase ofthe oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by theaddition of LF, a biochemical modulator of 5-FU activity.Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to theinduction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. Thestrategies based upon the use of scavengers could be used in order to prevent this effect.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
