Inhibition of Glucose Transporters and Glutaminase Synergistically Impairs Tumor Cell Growth. Issue 9 (19th September 2019)

• Record Type: Journal Article
• Authors: Reckzeh, Elena S.; Karageorgis, George; Schwalfenberg, Melanie; Ceballos, Javier; Nowacki, Jessica; Stroet, Marcus C.M.; Binici, Aylin; Knauer, Lena; Brand, Silke; Choidas, Axel; Strohmann, Carsten; Ziegler, Slava; Waldmann, Herbert
• Is Part Of: Cell chemical biology. Volume 26:Issue 9(2019)
• Page Start: 1214
• Page End: 1228.e25
• Publication Date: 2019-09-19
• Subjects: Warburg effect -- GLUT-1 -- GLUT-3 -- small molecule -- glutaminase -- co-treatment -- metabolic plasticity; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.06.005
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Cancer cells sustain growth by altering their metabolism to accelerated aerobic glycolysis accompanied by increased glucose demand and employ glutamine as additional nutrient source. This metabolic adaptation induces upregulation of glucose transporters GLUT-1 and -3, and simultaneous targeting of both transporters and of glutamine metabolism may offer a promising approach to inhibit cancer cell growth. We describe the discovery of the very potent glucose uptake inhibitor Glutor, which targets glucose transporters GLUT-1, -2, and -3, attenuates glycolytic flux and potently and selectively suppresses growth of a variety of cancer cell lines. Co-treatment of colon cancer cells with Glutor and glutaminase inhibitor CB-839 very potently and synergistically inhibits cancer cell growth. Such a dual inhibition promises to be particularly effective because it targets the metabolic plasticity as well as metabolic rescue mechanisms in cancer cells. Graphical Abstract: Highlights: Development of the GLUT-1-3-selective inhibitor Glutor to suppress glucose uptake Glutor potently induces cell death in 2D and 3D cancer cell culture Glutor-induced hypoglycemia upregulates GLUT-1/-3 Glutor and GLS inhibitor CB-839 synergistically inhibit cell growth Abstract : Cell-based screening identified the piperazin-2-one Glutor as a nanomolar inhibitor of glucose uptake that targets the glucose transporters GLUT-1/-3. Glutor inhibits glycolysis and effectively incudes cell death of monolayer- and spheroid-cultured cancer cells. Glutor-mediated glucose starvation upregulates GLUT-1/-3 expression. Glutor and glutaminase inhibitor CB-839 synergistically inhibit cancer cell growth.