TVP1022 and propargylamine protect neonatal rat ventricular myocytes against doxorubicin-induced and serum starvation-induced cardiotoxicity.
We recently reported that propargylamine derivatives such as rasagiline (Azilect) and its S-isomer TVP1022 are neuroprotective. The aim of this study was to test the hypothesis that the neuroprotective agents TVP1022 and propargylamine (the active moiety of propargylamine derivatives) are also cardioprotective. We specifically investigated the protective efficacy of TVP1022 and propargylamine in neonatal rat ventricular myocytes (NRVM) against apoptosis induced by the anthracycline chemotherapeutic agent doxorubicin and by serum starvation. We demonstrated that pretreatment of NRVM cultures with TVP1022 or propargylamine attenuated doxorubicin-induced and serum starvation-induced apoptosis, inhibited the increase in cleaved caspase 3 levels, and reversed the decline in Bcl-2/Bax ratio. These cytoprotective effects were shown to reside in the propargylamine moiety. Finally, we showed that TVP1022 neither caused proliferation of the human cancer cell lines HeLa and MDA-231 nor interfered with the anti-cancer efficacy of doxorubicin. These results suggest that TVP1022 should be considered as a novel cardioprotective agent against ischemic insults and against anthracycline cardiotoxicity and can be coadministered with doxorubicin in the treatment of human malignancies.
Kleiner
Yana
Y
Department of Physiology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel.
Bar-Am
Orit
O
Amit
Tamar
T
Berdichevski
Alexandra
A
Liani
Esti
E
Maor
Gila
G
Reiter
Irina
I
Youdim
Moussa B H
MB
Binah
Ofer
O
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006331:Heart Diseases / Q000188:drug therapy* / Q000209:etiology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D007189:Indans; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C031967:rasagiline; C009054:propargylamine; D004317:Doxorubicin; D010293:Pargyline; D053148:Caspase 3