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.

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

“…As a second-generation Bcr-Abl inhibitor, nilotinib mediated apoptosis mainly through the accumulation of ROS and ER stress (Doherty et al, 2013). The increase of ROS and ER stress biomarkers (ATF4 and CHOP), was observed in nilotinib-treated H9c2 cells, which subsequently decreased MMP and activated caspase-3, markers of apoptosis (Lekes et al, 2016). Recently, Yang et al (2018) made further efforts to demonstrate that nilotinib induced ER stress to activate JNK and restrain Akt phosphorylation, which in turn suppressed glycogen synthase kinase-3 beta (GSK3β) phosphorylation and activated NOX4/ROS signaling, resulting in apoptosis.…”

Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

“…Tyrosine kinases inhibitors (TKI) are a novel class of anticancer drugs targeting cellular pathways over-expressed in various types of malignancies [9]. Nilotinib, is an important second-generation tyrosine kinase inhibitor (TKI), widely used in the treatment of chronic myeloid leukaemia (CML) [9].…”

“…Tyrosine kinases inhibitors (TKI) are a novel class of anticancer drugs targeting cellular pathways over-expressed in various types of malignancies [9]. Nilotinib, is an important second-generation tyrosine kinase inhibitor (TKI), widely used in the treatment of chronic myeloid leukaemia (CML) [9]. It has been reported that nilotinib (Scheme 1) is the next generation of imatinib, as the first approved inhibitor of BCR-ABL, tyrosine kinase, determined the age of treatment of CML, and later studies determined its additional activity in targeting c-Kit and platelet-derived growth factor receptors (PDGFRs) [10].…”

Potentially Cardiotoxic Diterpenoid Alkaloids from the Roots of Aconitum carmichaelii

“…The elemental formula of compound 3 was determined as C 38 H 47 NO 12 from an observed protonated molecular ion at m/ z 710.3169 (calcd 710.3171, [M + H] + ). The 1 H and 13 C NMR data showed the presence of signals for two sets of benzoyl units, four methoxy groups, and an N-methyl group (Table 2). Except for the above signals, 19 carbon signals remained; thus compound 3 was postulated to be a C 19diterpenoid alkaloid.…”