טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentZiv Doron
SubjectThe cardioprotective efficacy of TVP1022 against the
cardiotoxicity caused by the anti-cancer
tyrosine kinase inhibitors
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Ofer Binah
Full Thesis textFull thesis text - English Version


Abstract

Over the last decade, the small molecule tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers, such as chronic myeloid leukemia (CML) and other hematological cancers. However, during the past years it has become evident that some of the TKIs, such as imatinib and sunitinib, cause severe side effects encompassing left ventricular dysfunction leading to heart failure and electrocardiographic abnormalities include arrhythmias, hypertension, hypertrophy and mitochondrial damage.   TVP1022 (the S-isomer of rasagiline (Azilect?), FDA-approved anti-Parkinson drug) was found to exert a significant anti-apoptotic and cytoprotective efficacy in in vitro cultures of neuronal cells and cardiomyocytes, as well as cardioprotective activities against various cardiac insults such as chronic heart failure and Ischemia/reperfusion in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against the cardiotoxicity of the investigated TKIs, imatinib and sunitinib. Accordingly, the aim of the study was to investigate in vitro the cardioprotective efficacy of TVP1022 against the cardiotoxic damage caused by imatinib and sunitinib to cardiomyocytes.

The effect of TVP1022 was tested in induced-Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) and on the [Ca2]i transient parameters by means of the FURA-2 system. Imatinib and sunitinib were tested for their cardiotoxicities at acute and chronic treatments. The results show, in general, that TVP1022 does not protect against the cardiotoxicity of these drugs, except for a significant protection against the acute effect of imatinib.