2. Academic Validation
  3. Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid

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

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2829-2833. doi: 10.1016/j.bmcl.2016.04.062.
Surendra R Punganuru 1,  A G M Mostofa 1,  Hanumantha Rao Madala 1,  Debasish Basak 1,  Kalkunte S Srivenugopal 2
Affiliations

Affiliations

  • 1 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.
  • 2 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: Kalkunte.Srivenugopal@ttuihsc.edu.
PMID: 27156773 DOI: 10.1016/j.bmcl.2016.04.062
Abstract

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.

Keywords

2-Amino-2-deoxy-d-glucose; Cell cycle arrest; Ethacrynic acid; GSTP1; Reactive oxygen species; Redox-stress.

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