title: Nilotinib induces ER stress and cell death in H9c2 cells.
abstract: Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations. In addition, ability of nilotinib to induce ER stress has been shown. These events result in apoptotic cell death. All these mechanisms contribute to cytotoxic effect of the drug. In addition, involvement of ER stress in nilotinib toxicity may be important in co-treatment with pharmaceuticals affecting ER and ER stress, e.g. beta-blockers or sartans, and should be further investigated.
authors.affiliation: Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. babula@med.muni.cz.
authors.forename: D
authors.initials: D
authors.lastname: Lekes
authors.forename: I
authors.initials: I
authors.lastname: Szadvari
authors.forename: O
authors.initials: O
authors.lastname: Krizanova
authors.forename: K
authors.initials: K
authors.lastname: Lopusna
authors.forename: I
authors.initials: I
authors.lastname: Rezuchova
authors.forename: M
authors.initials: M
authors.lastname: Novakova
authors.forename: Z
authors.initials: Z
authors.lastname: Novakova
authors.forename: T
authors.initials: T
authors.lastname: Parak
authors.forename: P
authors.initials: P
authors.lastname: Babula
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats
chemical_list: D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C498826:nilotinib