A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Abstract

The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATPsensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.

Evidence for the Role of Intracellular Water Lifetime as a Tumour Biomarker Obtained by In Vivo Field‐Cycling Relaxometry

“…Cells were incubated for 24 h in the presence of 5 μ m of WZB117,13 the GLUT‐1 inhibitor, or 100 μ m of Ouabain,14 the Na + /K + ATPase inhibitor. Then, τ in was determined on the cell lines “in vitro” following the above described procedure.…”

Endothelial cell metabolism inhibition: A new approach to the treatment of resistant metastatic colorectal carcinoma

“…These include GLUT1-targeted therapeutic agents such as small chemical entities, as well as GLUT1-mediated target drug delivery for anticancer agents such as fluorine-substituted platinum(II)-sugar conjugates. WZB117 and STF-31 have been shown as novel small molecules with highest affinities for sugar transport inhibition that are able to efficiently block tumor growth when used in mouse models without significant adverse events in treated animals [20,21] . Additionally, fluorine-substituted series of glucose-, mannose-and galactose-conjugated platinum(II) complexes have been designed and synthesized to leverage GLUT1-mediated specific drug uptake, utilizing the metabolic disparity between normal and malignant cells [22] .…”

Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases

“…Such approaches have to be specific for GLUT1 in cancer cells and not have adverse effects on glycolytic activity in normal cells. Cancer cells treated with WZB117 had decreased levels of GLUT1 expression, intracellular ATP and glycolytic enzymes resulting in a lowered rate of glycolysis and cellular growth [169].…”