Fig. 7: Glutathione metabolism modulates the sensitivity to BH3 mimetics.

A Schematic depiction of glutathione metabolism in human cells. The enzyme glutamate-cysteine ligase (GCL) produces γ-glutamylcysteine from glutamate and cysteine. Then, glutathione synthetase (GSS) adds glycine to the C-terminus of γ-glutamylcysteine to form reduced glutathione (GSH), which can be oxidized to GSSG or conjugated to xenobiotic compounds by glutathione-S-transferases (GSTs). The synthesis of GSH can be inhibited using the GCL inhibitor Buthionine sulfoximine (BSO), while GSH-conjugation to drugs can be inhibited using the GSTs inhibitor Ethacrynic acid (EA). Figure was created using bioRender.com. B Growth curves of MOLM-13 cells treated with DMSO, 100 µM BSO, Venetoclax (increasing concentrations 1, 5 and 10 nM) or Venetoclax in combination with 100 µM BSO. Data are presented as mean values ± SD. n = 2 experimental replicates. C Growth curves of Venetoclax-resistant MOLM-13 cells treated with DMSO, 100 µM BSO, 1 µM Venetoclax or 1 µM Venetoclax in combination with 100 µM BSO. Data are presented as mean values ± SD. n = 3 experimental replicates. D Growth curves of MOLM-13-Cas9 knockout clones AAVS1.1 (left), ABCC1-KO-2 (right) treated with DMSO, 100 µM BSO, Venetoclax (increasing concentrations 1, 5 and 10 nM) or Venetoclax in combination with 100 µM BSO. Data are presented as mean values ± SD. n = 2 experimental replicates. E Relative viability of primary patient-derived AML cells treated with Venetoclax (left) or AZD-4320 (right) in combination with DMSO or 100 µM BSO for 3 days. Concentrations used were: patient 1: 9.8 nM Venetoclax and 2.4 nM AZD-4320; patient 2: 39 nM Venetoclax and 39 nM AZD-4320. Data were normalized to DMSO-treated controls and are presented as mean values ± SD. n = 3 experimental replicates. B–E Source data are provided as a Source Data file.