Drug Resistance of Endocardial Endothelial Cells is Related to Higher Endogenous ABCG2

• Published in: Cardiovascular toxicology Vol. 16; no. 4; pp. 390 - 405
• Main Authors: Ajithkumar, G. S., Vinitha, A., Binil Raj, S. S., Kartha, C. C.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2016; Springer; Springer Nature B.V
• Subjects: ABC transporters; Animals; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Cardiology; Cell Line; Cell Survival - drug effects; Cells; Chromatin; Comparative analysis; Coronary vessels; Drug resistance; Drug Resistance, Neoplasm; Endocardium; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium; Glycoproteins; Heart; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Indoles - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Pharmacology/Toxicology; Swine; Up-Regulation; Veins & arteries; United States > US; India; Camptothecin; Fumitremorgin C; Pheophorbide-A; Doxorubicin; Endocardial endothelial cells; ABCG2; Apoptosis
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-015-9351-x

Endocardial endothelial cells (EECs), when compared with endothelial cells of arteries and veins, possess higher resistance to apoptosis-inducing anticancer agents. The mechanism of this resistance property is unknown. We have investigated the molecular mechanism, which contributes to increased cell survival capacity in EECs. We explored whether the resistance to apoptosis is associated with the cellular expression of ATP-binding cassette transporters such as P-glycoprotein, MRP-1, and ABCG2. We used primary and immortalized porcine endocardial endothelial cells (PEECs and hTERT PEECs) and compared the results with that in porcine aortic endothelial cells (PAECs), left atrioventricular valve endothelial cells (PVECs), and human umbilical vein endothelial cell line (EA.hy926). FACS and immunoblot analysis revealed a significantly higher expression of ABCG2 in PEECs and hTERT PEECs compared to PAECs, PVECs, and EA.hy926. Using apoptosis-inducing anticancer agents such as doxorubicin and camptothecin, through chromatin condensation assay and immunoblot analysis, we demonstrated a higher resistance to apoptosis in EECs compared to PAECs, PVECs, and EA.hy926. Interestingly, resistance in EECs reversed in presence of ABCG2 specific inhibitor, fumitremorgin C. Our observations suggest that an inherently high expression of ABCG2 in EECs protects them against apoptosis in presence of anticancer agents.