title: Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes.
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.
authors: Science and Technology Center, IRCCS MultiMedica, Milan, Italy.
authors: Chiara
authors: C
authors: Focaccetti
authors: Science and Technology Center, IRCCS MultiMedica, Milan, Italy.
authors: Antonino
authors: A
authors: Bruno
authors: Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors: Elena
authors: E
authors: Magnani
authors: Science and Technology Center, IRCCS MultiMedica, Milan, Italy.
authors: Desirée
authors: D
authors: Bartolini
authors: Science and Technology Center, IRCCS MultiMedica, Milan, Italy.
authors: Elisa
authors: E
authors: Principi
authors: Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors: Katiuscia
authors: K
authors: Dallaglio
authors: Oncology Unit, IRCCS MultiMedica, Castellanza, VA, Italy.
authors: Eraldo O
authors: EO
authors: Bucci
authors: Department of Pathology, Ospedale del Circolo, Varese, Italy.
authors: Giovanna
authors: G
authors: Finzi
authors: Department of Pathology, Ospedale del Circolo, Varese, Italy; Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors: Fausto
authors: F
authors: Sessa
authors: Science and Technology Center, IRCCS MultiMedica, Milan, Italy; Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
authors: Douglas M
authors: DM
authors: Noonan
authors: Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors: Adriana
authors: A
authors: Albini
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D005472:Fluorouracil