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

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Abstract

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.

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Acknowledgments

This study was funded by Department of Biotechnology, Government of India (DBT Sanction No. BT/PR13582/MED/30/285/2010). Ajith Kumar G.S. received Senior Research Fellowship from Council of Scientific and Industrial Research, Government of India. Binilraj S.S. was supported with Senior Research Fellowship from Indian Council of Medical Research, Government of India. Authors also acknowledge Prof. Edgell, (Pathology Department, University of North Carolina, Chapel Hill, USA) for the kind supply of EAhy.926 cell line and Dr. T.R. Santhosh Kumar for the scientific and technical inputs that helped in the improved execution of the study.

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  1. Cardiovascular Disease Biology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud. P.O, Trivandrum, Kerala, 695014, India

    G. S. Ajithkumar, A. Vinitha, S. S. Binil Raj & C. C. Kartha

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  1. G. S. Ajithkumar
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  2. A. Vinitha
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  3. S. S. Binil Raj
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Correspondence to G. S. Ajithkumar or C. C. Kartha.

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Ajithkumar, G.S., Vinitha, A., Binil Raj, S.S. et al. Drug Resistance of Endocardial Endothelial Cells is Related to Higher Endogenous ABCG2. Cardiovasc Toxicol 16, 390–405 (2016). https://doi.org/10.1007/s12012-015-9351-x

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