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. 2023 Aug 18;4(9):101162. doi: 10.1016/j.xcrm.2023.101162

Figure 6.

Figure 6

Pharmacological inhibition of GLUT1 or G6PD enhances chemotherapy sensitivity

(A) GLUT1 knockdown suppresses tumorigenesis in a DAC-42 ODX model (n = 6 per group).

(B) The effect of the GLUT1 inhibitor BAY-876 (50 nM) on extracellular glucose consumption in DAC-18 (lipomet) and DAC-42 (glucomet) organoids was evaluated (n = 4).

(C) Effect of BAY-876 (50 nM) on the GEM responsiveness of DAC-42 (glucomet) and DAC-18 (lipomet) as determined by CellTiter-Glo assays 120 h after treatment with GEM.

(D) The effect of 6AN on G6PD activity in DAC-42 (glucomet) organoids was evaluated (n = 4).

(E) Effect of 6AN treatment on the 5-FU responsiveness of DAC-42 (glucomet) organoids as determined by CellTiter-Glo assays 120 h after treatment with 5-FU.

(F) Effect of 6AN on 5-FU responsiveness in the ODX model. Tumor volumes measured by calipers at the indicated time points in tumor-implanted mice subjected to treatments with vehicle, 5-FU alone (25 mg/kg, every 2 days), 6AN alone (5 mg/kg, every 2 days), or 5-FU with 6AN.

(G) Normalized body weights of SCID mice with the indicated treatments.

(H) Volcano plot showing the effect of 40 compounds on the 5-FU responsiveness of DAC-34 (glucomet) as determined by CellTiter-Glo assays 120 h after treatment with compounds (5 μM), 5-FU (100 μM), or both.

(I) Prediction of the potential interaction sites in the 3D structure of the G6PD protein with 6AN, MLN8054, and alisertib.

(J) Effect of MLN8054 and alisertib on G6PD activity in DAC-42 (glucomet) organoids.

(K) Effect of MLN8054 or alisertib treatment on the 5-FU responsiveness of DAC-42 (glucomet) as determined by CellTiter-Glo assays 120 h after treatment with the indicated drugs.

(L) Tumor volume of DAC-42 ODXs (n = 6 per group) in SCID mice following treatment with the indicated drugs.

(M) Normalized body weights of SCID mice (n = 3 per group) with the indicated treatments.

(N) Tumor volume of DAC-18 ODXs (n = 6 per group) in SCID mice following treatment with the indicated drugs.

(O) Normalized body weights of SCID mice (n = 3 per group) with the indicated treatments.

All dose-responsive curves were performed with 3 technical replicates. Data are presented as the mean values ± SEMs, and statistical significance was computed by unpaired Student’s t test (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001) (A–G and J–O).