Nilotinib induces ER stress and cell death in H9c2 cells
D Lekes1, I Szadvari, O Krizanova
1Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. babula@med.muni.cz.
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.
Insights
Nilotinib, a tyrosine kinase inhibitor, causes cardiotoxicity by impairing mitochondrial function and inducing endoplasmic reticulum stress and apoptosis in H9c2 cells. This suggests potential risks when combined with other ER-targeting drugs.
Area of Science:
- Pharmacology
- Cell Biology
- Toxicology
Background:
- Tyrosine kinase inhibitors (TKIs) are novel anticancer drugs targeting specific cellular pathways.
- Nilotinib, imatinib, and ponatinib are TKIs known to cause cardiotoxic and vascular effects.
- Chronic myeloid leukemia (CML) is a malignancy where TKIs are commonly used.
Purpose of the Study:
- To investigate the potential cardiotoxicity of nilotinib.
- To elucidate the role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib-induced toxicity.
- To utilize H9c2 cells as a relevant cell model for studying nilotinib's effects.
Main Methods:
- Utilized H9c2 cells as a cellular model for cardiotoxicity assessment.
- Employed a complex approach to study ER stress and apoptosis.
- Assessed mitochondrial function and reactive oxygen species (ROS) formation.
- Investigated nilotinib's cytotoxic effects at clinically relevant concentrations.
Main Results:
- Nilotinib impaired mitochondrial function in H9c2 cells.
- Clinically relevant concentrations of nilotinib induced reactive oxygen species (ROS) formation.
- Nilotinib was shown to induce endoplasmic reticulum (ER) stress.
- These cellular events led to apoptotic cell death, contributing to nilotinib's cytotoxic effect.
Conclusions:
- Nilotinib exhibits cardiotoxicity through mechanisms involving mitochondrial dysfunction, ROS production, and ER stress, culminating in apoptosis.
- The induction of ER stress by nilotinib may have implications for co-treatment strategies with drugs affecting ER function.
- Further research is warranted to explore the interaction of nilotinib with other pharmaceuticals, particularly those impacting ER and ER stress pathways.
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