Inhibition of Glucose Transporters and Glutaminase Synergistically Impairs Tumor Cell Growth

Abstract

Highlights d Development of the GLUT-1-3-selective inhibitor Glutor to suppress glucose uptake d Glutor potently induces cell death in 2D and 3D cancer cell culture d Glutor-induced hypoglycemia upregulates GLUT-1/-3 d Glutor and GLS inhibitor CB-839 synergistically inhibit cell growth

Synthesis of Indomorphan Pseudo‐Natural Product Inhibitors of Glucose Transporters GLUT‐1 and ‐3

“…Moreover, induction of GLUT3 expression has been reported to be a protective mechanism against hypoglycemia in neurons, and cancer cells respond similarly to decreased glucose levels . Thus, efficient inhibition of glucose uptake in tumors and cancer cells may require simultaneous targeting of both GLUT‐1 and GLUT‐3, and we recently developed the first GLUT‐1/GLUT‐3‐selective compounds …”

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

“…This adaptation mechanism was mimicked by the treatment with 0.5 μ m glutor and 0.5 μ m glupin, respectively . GLUT4 mRNA stayed unaltered and GLUT2 mRNA was not detectable in these cells, indicating a low relevance for this isoform under hypoglycemic conditions . Similar outcomes were observed previously in glucose‐deprived neuronal rat cells and in MCF7 and HeLa cells cultured under reduced (2.5 m m ) glucose concentration .…”

“…Many cancers show high metabolic plasticity, because mitochondria are usually still functional and can use alternative nutrients for energy production and biosynthesis . To explore synergistic targeting of several metabolic pathways, the glucose uptake inhibitor glutor was combined with CB‐839, a small‐molecule inhibitor that targets the kidney glutaminase isoform which is overexpressed in many cancers, to suppress the growth of HCT116 cells . The combination of glutor with CB‐839 decreased the GI 50 value of glutor from 428 n m (0 μ m CB‐839) by about 40‐fold to GI 50 =10 n m (5 μ m CB‐839) .…”

“…To explore synergistic targeting of several metabolic pathways, the glucose uptake inhibitor glutor was combined with CB‐839, a small‐molecule inhibitor that targets the kidney glutaminase isoform which is overexpressed in many cancers, to suppress the growth of HCT116 cells . The combination of glutor with CB‐839 decreased the GI 50 value of glutor from 428 n m (0 μ m CB‐839) by about 40‐fold to GI 50 =10 n m (5 μ m CB‐839) . Inhibition of the glutaminase disrupts the supply of α‐ketoglutarate to the TCA cycle and therefore interferes with an alternative metabolic pathway for energy production.…”

“…[28] Waldmann et al also discoveredp iperazin-2-one-derived inhibitors in the same cell-based assay.T he most active member, glutor (IC 50 = 11 nm,F igure 2, Table 1), targets GLUT-1, -2 and-3 ( Table 2). [27,29] Cell line sensitivity was tested using 94 different cell lines using as ulforhodamine Ba ssay for 72 ho fg lutor treatment, and revealed that the nonmalignant cell line IMR-90 and peripheral blood mononucleated cells (PBMCs) wereresistant (IC 50 > 30 mm)t ot reatment with glutor,w hereas nearly half of the malignant cell lines exhibited IC 50 < 100 nm (Table 2). [29] The urinary bladder carcinomac ell line UM-UC-3 and MIA PaCa-2 cells were mosts ensitive (IC 50 = 4nm,T able 2).…”