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

Bioorg Med Chem Lett

Department of Biomedical Sciences and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter Dr., Amarillo, TX 79106, USA. Electronic address:

Published: June 2016

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.

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Source
http://dx.doi.org/10.1016/j.bmcl.2016.04.062DOI Listing

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