5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress

Abstract

BackgroundCardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil(5-FU) and it can have detrimental effects both in patients and workers involved in the preparation of chemotherapy.MethodsSpecifically, we have assessed the effects of increasing concentrations of 5-FU and doxorubicin (DOXO) on proliferation of H9c2 rat cardiocytes and HT-29 human colon adenocarcinoma cells by MTT assay. Cells were treated for 24, 48 and 72 h with different concentrations of the two drugs alone or with 5-FU in combination with 10-4 M of levofolene (LF).Results5-FU induced a time- and dose-dependent growth inhibition in both cell lines. The 50% growth inhibition (IC:50) was reached at 72 h with concentrations of 4 μM and 400 μM on HT-29 and H9c2, respectively. The addition of LF to 5-FU enhanced this effect. On the other hand, the IC:50 of DOXO was reached at 72 h with concentrations of 0.118 μM on H9c2 and of 0.31 μM for HT-29. We have evaluated the cell death mechanism induced by 50% growth inhibitory concentrations of 5-FU or DOXO in cardiocytes and colon cancer cells. We have found that the treatment with 400 μM 5-FU induced apoptosis in 32% of H9c2 cells. This effect was increased by the addition of LF to 5-FU (38% of apoptotic cells). Apoptosis occurred in only about 10% of HT-29 cells treated with either 5-FU or 5-FU and LF in combination. DOXO induced poor effects on apoptosis of both H9c2 and HT-29 cells (5–7% apoptotic cells, respectively). The apoptosis induced by 5-FU and LF in cardiocytes was paralleled by the activation of caspases 3, 9 and 7 and by the intracellular increase of O2− levels.ConclusionsThese results suggest that cardiotoxic mechanism of chemotherapy agents are different and this disclose a new scenario for prevention of this complication.

Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

“…Several studies have shown that intracellular ROS levels increase in response to FUra (Hwang et al, 2001;Liu and Chen, 2002;Akhdar et al, 2009;Matsunaga et al, 2010;Lamberti et al, 2012). However, it has not been determined whether such increases are due to inhibition of TYMS as opposed to other effects of the antimetabolite.…”

“…Studies by Liu and Chen (2002) similarly suggested that FDXR promotes ROS-mediated apoptosis in response to FUra in a p53-dependent fashion. Despite these interesting studies as well as others showing increased ROS levels after exposure to FUra (Akhdar et al, 2009;Matsunaga et al, 2010;Lamberti et al, 2012), we still lack a detailed mechanistic understanding of how exposure to TYMS inhibitors alters the intracellular redox environment, and how cells respond to such alterations. Currently, we have examined ROSmediated oxidative stress and its function in apoptotic cell death induced by TYMS inhibitors.…”

Evaluation of cardioprotective activity of Lepidium sativum seed powder in albino rats treated with 5-fluorouracil

“…Recent studies have suggested that the 5-FU-induced cytotoxicity is linked to the enhanced ROS formation as 5-FU increased intracellular levels of superoxide anion (O -2) (Afzal et al, 2012). As a consequence, the triggering of apoptotic program and cardiomyocyte damage were occurring (Lamberti et al, 2012). However, the exact molecular mechanisms of 5-FU cardiotoxicity have not yet been completely understood.…”

Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5‑Fluorouracil

“…2,5 The exact mechanism is currently unclear, but the authors of a systematic review 5 have proposed multifactorial underlying causes, including endothelium-dependent and -independent pathways, direct myocardial damage from cytotoxic effects, induction of apoptosis, rheological side effects, and the production, during drug storage, of cardiotoxic metabolite precursors (for example, fluoro acetate). [6][7][8][9][10][11][12] Animal models of 5-FU cardiotoxicity have manifested apoptosis of myocytes, endothelial cells, or both, which gives rise to clinical presentations similar to that of myocarditis. 12 The toxicity of 5-FU is dependent on the duration of treatment, on the rate of administration, or both; continuous infusions have higher incidences than do bolus regimens.…”