Abstract 1442: Effects of selective and broad glucose transporter (GLUT) inhibition on glucose distribution in tumor bearing mice

Abstract

Abstract Malignant cells are known for their accelerated metabolism, high energy requirements, and increased glucose uptake. Transport of glucose across the plasma membrane is the first and rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose uptake in malignant cells has been associated with upregulated expression of glucose transporters, mainly overexpression of GLUT1 and/or GLUT3. There is limited knowledge about how selective (e.g. GLUT1) versus broad (multi-) GLUT inhibition affects glucose homeostasis in tumor bearing mice. Using potent small molecule inhibitors, we compared [14C]-2-Deoxy-D-Glucose (2-DG) distribution after selective GLUT1 versus GLUT1, 3 and 4 [multi-GLUT] inhibition and versus control in human NSCLC NCI-H460 tumor bearing mice. A single dose of a GLUT1 selective and a multi-GLUT inhibitor were administered to NCI-H460 tumor bearing NMRI nu/nu mice. At the respective Cmax concentrations, a bolus of 2-DG was rapidly injected intra-peritoneally and the distribution of metabolically stable 2-DG was obtained using whole-body autoradiography after 15 min and 120 min. With the multi-GLUT inhibitor only a very short inhibition of 2-DG uptake was observed in the NCI-H460 tumors while a long-lasting inhibition was detected in heart, brain and brown fat tissue. In contrast, a long-lasting inhibition of 2-DG uptake was observed in NCI-H460 tumors for the selective GLUT1 inhibitor. 2-DG concentrations were reduced in the brain following administration of the selective GLUT1 inhibitor at 15 min and returned to normal levels at 120 min while the tumor 2-DG concentration stayed low. The 2-DG findings go in parallel with the histopathological findings present in the brain and heart after treatment with the multi-GLUT inhibitor. However, similar histopathological findings have not been observed in the brain and heart after treatment with the selective GLUT-1 inhibitor. Therefore, selective GLUT1 inhibition is associated with a sustained low 2-DG concentration in the NCI-H460 tumors while only minor changes in glucose homeostasis were observed in other organ systems. Citation Format: Melanie Heroult, Wolfram Steinke, Anna-Lena Frisk, Sandra Borkowski, Kirstin Meyer, Heike Petrul, Iring Heisler, Maria Quanz, Roland Neuhaus, Bernd Buchmann, Thomas Mueller, Marcus Bauser, Andrea Haegebarth, Michael Brands, Karl Ziegelbauer. Effects of selective and broad glucose transporter (GLUT) inhibition on glucose distribution in tumor bearing mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2014-1442