Pyridoxal isonicotinoyl hydrazone (PIH) is a new tridentate Fe-chelating agent that should be very promising in many pathological states resulting from both an iron-overload and formation of free radicals. The aim of our study was to investigate the effect of PIH on the cardiovascular system focusing to the regulatory protein - cardiac troponin T (cTnT). The study was carried out in two groups of Chinchilla male rabbits: 1) PIH (50 mg/kg dissolved in 10 % Cremophor i.p., once a week, 10 administrations, n=8) and 2) Cremophor (2 ml/kg i.p. in the same schedule, n=7). Plasma concentrations of cTnT (as a marker of myocardial damage) were measured using a commercial kit (Roche). cTnT was within the physiological range (i.e. < 0.1 mg/l) during the whole experiment in the Cremophor group. In the PIH group, the cTnT levels were not significantly increased when compared with the control group or with the initial values (except with those before the 5th administration). Furthermore, we analyzed the cytosolic and myofibrillar fraction of cTnT in the left ventricular myocardium. Using SDS-PAGE and Western blot we resolved three isoforms. The profiling of TnT did not differ significantly between the PIH-treated group and the Cremophor-treated group. Our data concerning cTnT support the opinion that the possible cardiotoxicity of PIH is very low., M. Adamcová, J. Macháčková, V. Geršl, V. Pelouch, T. Šimůnek, I. Klimtová, R. Hrdina, P. Poňka., and Obsahuje bibliografii
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 H9
c2 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.