Differential toxicity of anthracyclines on cultured endothelial cells.
Anthracyclines are known for their endothelial toxicity. Newer derivatives may have fewer toxic effects on endothelium. The authors therefore evaluated the effects of doxorubicin, doxorubicin analogs (daunorubicin, idarubicin), and pegylated liposomal doxorubicin (doxil) in human coronary artery endothelial cells (HCAECs). Endothelial viability did not change significantly with doxil, but was decreased with doxorubicin, daunorubicin, or idamycin. Similarly caspase-3 activity was significantly elevated in HCAECs treated with doxorubicin, daunorubicin, and idamycin. In contrast, doxil did not cause significant increase in caspase activity. The authors also characterized the levels of antiapoptotic and prosurvival proteins using Western blot analysis. There was no significant difference in the expression levels of Bcl-2, Bax, and phospho-Akt in endothelial cells treated with anthracycline derivatives. However, the expression levels of Mcl-l protein were unaltered in endothelial cells treated with doxil but were significantly decreased when treated with other anthracycline analogs. Doxil minimally affected the expression levels of p53, whereas other anthracyclines induced p53 protein levels to a significant level, resulting in endothelial cell apoptosis. The authors conclude that the liposomal anthracycline protects endothelial cells from injury by preventing caspase-3 activation and maintaining the expression of antiapoptotic molecule Mcl-1.
Kaushal
Varsha
V
Division of Hematology/Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA. Kaushalvarsha@uams.edu
Kaushal
G P
GP
Mehta
Paulette
P
D018943:Anthracyclines / Q000378:metabolism / Q000633:toxicity*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018943:Anthracyclines; D016159:Tumor Suppressor Protein p53; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases