Lekes D, Szadvari I, Krizanova O, Lopusna K, Rezuchova I, Novakova M, Novakova Z, Parak T, Babula P
Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Physiol Res. 2016 Dec 21;65(Suppl 4):S505-S514. doi: 10.33549/physiolres.933504.
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.
酪氨酸激酶抑制剂（TKi）是一类相对新颖的抗癌药物，其作用靶点是某些类型恶性肿瘤（如慢性髓性白血病（CML））中过表达的细胞通路。尼罗替尼、波纳替尼和伊马替尼具有心脏毒性和血管效应。在本研究中，我们以H9c2细胞作为合适的细胞模型，重点研究尼罗替尼可能的心脏毒性。我们采用综合方法研究内质网（ER）应激和凋亡在尼罗替尼毒性中的作用。尼罗替尼在临床相关浓度下会损害线粒体功能并诱导活性氧（ROS）的形成。此外，已有研究表明尼罗替尼具有诱导ER应激的能力。这些事件导致细胞凋亡死亡。所有这些机制都促成了该药物的细胞毒性作用。此外，ER应激在尼罗替尼毒性中的作用在与影响ER和ER应激的药物（如β受体阻滞剂或沙坦类药物）联合治疗中可能很重要，应进一步研究。
