The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis.

Abstract

Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

• Authors: Martina Monti, Erika Terzuoli, Marina Ziche, Lucia Morbidelli
• Journal: Pharmacological research (Pharmacol Res) Vol. 76 Pg. 171-81 (Oct 2013) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 23965518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013. Published by Elsevier Ltd.

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antibiotics, Antineoplastic
• Tumor Suppressor Protein p53
• zofenoprilate
• Doxorubicin
• Captopril
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Captopril (analogs & derivatives, pharmacology)
• Cattle
• Cell Line
• Cell Line, Tumor
• Coronary Vessels (cytology, drug effects)
• Doxorubicin (toxicity)
• Endothelium
• Endothelium, Vascular (drug effects, pathology)
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neoplasms (drug therapy)
• Tumor Suppressor Protein p53 (metabolism)