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Chemotherapy-induced Vascular Toxicity - Real-time In vivo Imaging of Vessel Impairment
Published on: January 7, 2015
Differential toxicity of anthracyclines on cultured endothelial cells
Varsha Kaushal1, G P Kaushal, Paulette Mehta
1Division 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
Abstract:
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.
Insights
Newer liposomal anthracyclines, like doxorubicin (doxil), show reduced endothelial toxicity compared to traditional anthracyclines. Doxil preserves endothelial cell viability and function by inhibiting apoptosis pathways.
Area of Science:
- Cardiology
- Oncology
- Cell Biology
Background:
- Anthracyclines are chemotherapy agents with known endothelial toxicity.
- Investigating newer anthracycline derivatives for improved safety profiles is crucial.
Purpose of the Study:
- To evaluate the endothelial toxicity of doxorubicin, its analogs (daunorubicin, idarubicin), and pegylated liposomal doxorubicin (doxil).
- To compare the effects on human coronary artery endothelial cells (HCAECs) viability, apoptosis, and protein expression.
Main Methods:
- Treatment of HCAECs with doxorubicin, daunorubicin, idarubicin, and doxil.
- Assessment of endothelial viability and caspase-3 activity.
- Western blot analysis for antiapoptotic (Bcl-2, Mcl-1) and prosurvival (phospho-Akt, p53) proteins.
Main Results:
- Doxil did not significantly decrease HCAEC viability or increase caspase-3 activity.
- Doxorubicin, daunorubicin, and idarubicin reduced viability and elevated caspase-3 activity.
- Doxil maintained Mcl-1 expression and minimally affected p53, unlike other anthracyclines.
Conclusions:
- Pegylated liposomal doxorubicin (doxil) demonstrates significantly less endothelial toxicity than traditional anthracyclines.
- Doxil protects endothelial cells by preventing caspase-3 activation and preserving Mcl-1 expression.
