Abstract
Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity.
Highlights
The antimetabolite 5-Fluorouracil (5-FU), an analogue of uracil, and its pro-drugs are widely used antineoplastic agents for the treatment of gastrointestinal cancers, breast, gynecological as well as head and neck tumors [1]. 5-FU availability for intracellular anabolism mainly depends on tissue drug catabolism
To shed light on some of the mechanisms of 5-FU cardiotoxocity, here we examined the effects of 5-FU on endothelial cells and cardiomyocytes in vitro and in a colorectal cancer xenograft model, analyzing both at cellular and molecular levels the mechanisms involved in cardio-vascular toxicity associated with 5FU treatment
5-Fluorouracil (5-FU), 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), the Toxicology Assay Kit (TOX7), Propidium Iodide (PI), the Senescence Cells Histochemical Staining Kit, 2',7'-dichlorodihydrofluorescein-diacetate (DCFH-DA), N-acetyl-L-cysteine (NAC), Acridine Orange (AO) and Vincristine were purchased from Sigma-Aldrich
Summary
The antimetabolite 5-Fluorouracil (5-FU), an analogue of uracil, and its pro-drugs are widely used antineoplastic agents for the treatment of gastrointestinal cancers, breast, gynecological as well as head and neck tumors [1]. 5-FU availability for intracellular anabolism mainly depends on tissue drug catabolism. Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine), an orally administered fluoropyrimidine carbamate 5-FU prodrug, is converted into 5-FU through sequential steps (S1 Fig.) with preferential activation in tumors because of tissue distribution of key metabolic enzymes, in particular Thymidine phosphorylase (TP) [3]. 5-FU acts during the S phase of the cell cycle inhibiting DNA synthesis by restricting availability of thymidylate (S1 Fig.). 5-Fluorouracil inhibits thymidylate synthetase through its metabolite 5-fluorodeoxyuridine monophosphate (FdUMP). FdUMP forms a covalent ternary complex with thymidylate synthetase and 5,10-methylene tetrahydrofolate. The non-linearity of 5-FU kinetics probably reflects the saturation level of metabolic processes or transport at the highest concentrations of the drug and represents the main reason justifying the difficulty in predicting the plasma levels or toxicity at high doses [10]
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