טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBerdichevski Alexandra
SubjectCardioprotective Efficacy of TVP1022 and Propargylamine
against Doxorubicin-Induced Cardiotoxicity
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Ofer Binah
Full Thesis textFull thesis text - English Version


Abstract

This thesis is about the cardioprotective efficacy of new anti-apoptotic cytoprotective compounds, TVP1022 and propargylamine, against doxorubicin-induced cardiotoxicity. Doxorubicin is of the most widely prescribed and effective chemotherapeutic agents utilized in oncology. However, prolonged use of doxorubicin can lead to chronic cardiotoxicity, leading to irreversible congestive heart failure with high mortality risk. Nevertheless, despite these deleterious side effects, the benefits of anthracyclines outweigh the risks, and thus doxorubicin continues to serve as an important anti-cancer drug. Thus, drugs aimed at minimizing its cardiotoxicity are actively sought. Based on the established cytoprotective efficacies of TVP1022 (the S-isomer of rasagiline, Azilect, FDA-approved anti-Parkinson drug) and propargylamine, its active moiety, we tested the hypothesis that TVP1022 will provide protection against doxorubicin-induced functional derangements in neonatal rat ventriculat myocytes (NRVM). We found that: 1. TVP1022 prevented doxorubicin-induced alterations in the [Ca2+]i transients, and contraction parameters in NRVM. 2. TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling. 3. TVP1022 prevented doxorubicin-induced derangements in activation and propagation patterns in spontaneously-beating cultures. 4. One of the mechanisms of TVP1022 cardioprotection is its effect on the expression of the key proteins of calcium homeostasis and intercellular communication in the heart: sarco/endoplasmic reticulum Ca2+ ATPase, Na+/Ca2+ exchanger 1 and total connexin43. 5. The protective efficacy of TVP1022 is due to its active moiety-propargylamine. 6. TVP1022 and propargylamine are potentially safe (once established in vivo) to use in oncologic patients, since they did not cause proliferation of cancer cells, did not affect cancer cell viability and did not interfere with the anti-cancer activity of doxorubicin. Conclusion: our results indicate that TVP1022 acts as a novel cardioprotective agent against cardiotoxicity of doxorubicin, and therefore potentially can be co-administered with doxorubicin in the treatment of human malignancies.