Ovarian Cancer Relies on Glucose Transporter 1 to Fuel Glycolysis and Growth: Anti-Tumor Activity of BAY-876

Abstract

The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent.

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

“…Ma et al. applied BAY‐876 to different ovarian cancer cell lines using an MTT assay and determined a growth inhibitory IC 50 value of 60 n m for OVCAR‐3 cells (Table ), whereas SKOV‐3 cells yielded an IC 50 value of 188 n m and A2780 cells were resistant to treatment . Hence, the potency of BAY‐876 seems to be cell line dependent.…”

“…Despite al oss of body weight, the mice showedn om ajor health impairment. [24] BAY-876 selectively inhibitsG LUT-1 in vitro and in vivo. However,c are should be takenw hen selecting an appropriate cell line.…”

“…Furthermore, daily treatment with 4.5 mg kg −1 BAY‐876 over 2 weeks decreased the tumor volume of SKOV‐3 xenograft models by 68 % (Table ). Despite a loss of body weight, the mice showed no major health impairment . BAY‐876 selectively inhibits GLUT‐1 in vitro and in vivo.…”

“…[ ent ovarian cancer cell lines using an MTT assay and determined ag rowth inhibitory IC 50 value of 60 nm for OVCAR-3 cells (Table 2), whereas SKOV-3c ells yieldeda nI C 50 value of 188 nm and A2780 cells werer esistant to treatment. [24] Hence, the potency of BAY-876 seems to be cell line dependent.F urthermore, daily treatment with 4.5 mg kg À1 BAY-876 over 2weeks decreased the tumor volumeo fS KOV-3 xenograft modelsb y6 8% (Table 2). Despite al oss of body weight, the mice showedn om ajor health impairment.…”

“…Mode of actionI C 50 /GI 50 viability/growth in vitro Furtherp reclinical data cytochalasin B [11] GLUT-1-4 [14a] non-competi-B 16F10 % 0.4 mm [b] [15] reducedt umorformation in mice at 10 and over 7 [14b] tive [a] [12b] 100 mg kg À1 , [15] inhibitor of actinpolymerization WZB117 [17b] GLUT-4 over competitive [a] A549 10-30 mm, [c] NL20 resistant increased cell sensitivity under hypoxicconditions GLUT-1/3 [12b] [12b] in vitro,7 0% tumorv olume reduction in xenograft models compound n.d. n.d. A549 < 126 nm (5 mm Glc) [d] -155 [19] GLUT-i1 [20] GLUT-1/4 n.d. n.d. co-crystalw ith hGLUT-1 GLUT-i2 [20] over GLUT-2/3 compound 3 [21b] GLUT-1/3 competitive n.d. over GLUT-2 BAY-876 [22a] GLUT-1 over competitive OVCAR-3 60 nm, [e] [24] BT549, MDA-MB-436, HCC70 68 %t umor volume reduction in SKOV-3 GLUT-2/3/4 resistant at 3 mm [d] [23] xenografti nmice after 2weeks( 4.5 mg kg À1 ) [24] example 31 [26] n. [27] over GLUT-2/4 MIA PaCa-2 2.8 mm (25 mm Glc), 0.6 mm (5 mm Glc) [d] glutor [29] GLUT-1-3 n.d. UM-UC-34n m, [f] MIA PaCa-2 4nm, [f] PBMCs and equallyp otent in 2D and 3D cell culture over GLUT-4IMR-90r esistanta t30mm, [f] 94 cell lines tested [f] glupin [30] GLUT-1/3 mixed-type UM-UC-33 2nm, [f] MIA PaCa-2 61 nm, [f] PBMCs and metabolomic measurement confirmedr eduction over GLUT-2/4 inhibitionI MR-90 resistanta t30mm [f] 94 cell lines tested [f] of glycolyticm etabolites in MOLT16 cells NV-5440 [31] GLUT-1- -3) or HEK293-T (hGLUT-4 to -5) cells using an ATPd epletion assay in the presence of rotenone. Control experiments revealed that glucosed epletion is responsible for the selective mTORC1 inhibition, which could be confirmed in vivo.…”