期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 12, 页码 2829-2833出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.04.062
关键词
Ethacrynic acid; 2-Amino-2-deoxy-D-glucose; Reactive oxygen species; GSTP1; Cell cycle arrest; Redox-stress
资金
- Cancer Prevention Research Institute of Texas [RP130266]
- Carson-Leslie Foundation
- Association for Research of Childhood Cancer
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. (C) 2016 Published by Elsevier Ltd.
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