title: Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid.
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.
authors.affiliation: 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.
authors.forename: Surendra R
authors.initials: SR
authors.lastname: Punganuru
authors.affiliation: 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.
authors.forename: A G M
authors.initials: AGM
authors.lastname: Mostofa
authors.affiliation: 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.
authors.forename: Hanumantha Rao
authors.initials: HR
authors.lastname: Madala
authors.affiliation: 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.
authors.forename: Debasish
authors.initials: D
authors.lastname: Basak
authors.affiliation: 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.
authors.forename: Kalkunte S
authors.initials: KS
authors.lastname: Srivenugopal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004976:Ethacrynic Acid / Q000138:chemical synthesis / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D004976:Ethacrynic Acid; D005944:Glucosamine
keywords: 2-Amino-2-deoxy-d-glucose; Cell cycle arrest; Ethacrynic acid; GSTP1; Reactive oxygen species; Redox-stress