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. 2023 Mar 1;61:102653. doi: 10.1016/j.redox.2023.102653

Fig. 2.

Fig. 2

Combination of lorlatinib and GPX4 inhibition drives melanoma ferroptosis.

(A-B) Indicated melanoma cells were treated with lorlatinib (5 μM), RSL3 (2.5 μM), or a combination of both drugs with or without cell death inhibitors (ZVAD-FMK, 5 μM; Necrostatin-1s, 10 μM; CQ, 10 μM; NAC, 1 mM; DFO, 100 μM) for 6h, and cell viability was assessed. (C) GPX4 deficient cells treated with different concentrations of lorlatinib for 12 h in the absence or presence of Fer-1 (2 μM), Lip-1 (10 μM) or DFO (100 μM). (D) Cell death of GPX4 deficient cells induced by the indicated treatment were shown by microscope and quantified by PI-staining coupled with flow cytometry. Lorlatinib, 5 μM; RSL3, 2.5 μM. (E-F) Real-time PCR analysis of CHAC1 (E) and PTGS2 (F) expression in A375 and SK-MEL-28 cells after the indicated treatment for 6 h. Lorlatinib, 5 μM; RSL3, 2.5 μM. (G) Analysis of MDA in A375 and SK-MEL-28 cells after the indicated treatment for 6 h. Lorlatinib, 5 μM; RSL3, 2.5 μM. (H) Lipid ROS were quantified with BODIPY-C11 using flow cytometry. Cells were treated as indicated for 6 h. Lorlatinib, 5 μM; RSL3, 2.5 μM. (I) Transmission electron microscopy images of A375 cells after the indicated treatment for 6 h. Lorlatinib, 5 μM; RSL3, 2.5 μM. Scale bar, upper, 2 μm; lower, 500 nm. One-way ANOVA analysis was performed in B, D, E, F, G. ***, P < 0.001.