Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid.

Ethacrynic acid (EA), a known inhibitor of the neoplastic marker glutathione S-transferase P1 and other GSTs, exerts a weak antiproliferative activity against human cancer cells. The clinical use of EA (Edecrin) as an anticancer drug is limited by its potent loop diuretic activity. In this study, we developed a non-diuretic 2-amino-2-deoxy-d-glucose conjugated EA (EAG) to target tumors cells via the highly expressed glucose transporter 1 (GLUT1). Cell survival assays revealed that EAG had little effect on normal cells, but was cytotoxic 3 to 4.5-fold greater than EA. Mechanistically, the EAG induced selective cell death in cancer cells by inhibiting GSTP1 and generating abundant reactive oxygen species. Furthermore, EAG induced p21(cip1) expression and a G2/M cell cycle block irrespective of the p53 gene status in tumor cells. These data encourage the development of new EA analogs. Copyright © 2016. Published by Elsevier Ltd.

Citation

Surendra R Punganuru, A G M Mostofa, Hanumantha Rao Madala, Debasish Basak, Kalkunte S Srivenugopal. Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid. Bioorganic & medicinal chemistry letters. 2016 Jun 15;26(12):2829-33

PMID: 27156773

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