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. Author manuscript; available in PMC: 2022 Dec 20.
Published in final edited form as: Chem Res Toxicol. 2021 Nov 24;34(12):2579–2591. doi: 10.1021/acs.chemrestox.1c00347

Figure 3.

Figure 3.

EET analogues 1-4 attenuate chronic cisplatin (CDDP) toxicity in LLC-PK1 proximal tubular cells in a time-dependent manner. Cells were pre-treated with vehicle (EtOH), analogues 1-4 (1 μM), or compound 5 (1 μM) for 1 h, followed by exposure to low (5 μM) or moderate (10 μM) concentrations of CDDP for 48, 72, or 96 h. (A) Compounds 2, 3, and 5 significantly maintained viability of LLC-PK1 cells exposed to 10 μM CDDP for 48 h (One way analysis of variance, Holm-Sidak method, *p < 0.05; **p < 0.01 vs. EtOH + CDDP group, α = 0.05). (B) Only analogues 2 and 3 significantly maintained viability of LLC-PK1 cells exposed to 10 μM CDDP for 72 h (One way analysis of variance, Holm-Sidak method, ***p < 0.001 vs. EtOH + CDDP group, α = 0.05). Their activity surpassed that of 5 (One way analysis of variance, Holm-Sidak method, †p < 0.05; ††p < 0.01 vs. 5 + CDDP group, α = 0.05), as the latter failed to display protective effects. Co-pre-treating 5 with an sEHI (t-AUCB) maintained activity of 5 (One way analysis of variance, Holm-Sidak method, ††p < 0.01 vs. 5 + CDDP group, α = 0.05) and significantly shielded cells (One way analysis of variance, Holm-Sidak method, ***p < 0.001 vs. EtOH + CDDP group, α = 0.05) (C) All four EET analogues 1-4, along with 5, significantly maintained viability of LLC-PK1 cells exposed to 5 μM CDDP for 72 h (One way analysis of variance, Holm-Sidak method, *p < 0.05; **p < 0.01; ***p < 0.001 vs. EtOH + CDDP group, α = 0.05). (D) Compounds 2, 3, 4, and 5 significantly maintained viability of LLC-PK1 cells exposed to 5 μM CDDP for 96 h (One way analysis of variance, Holm-Sidak method, *p < 0.05; ***p < 0.001 vs. EtOH + CDDP group, α = 0.05). Moreover, the activity of 2-4 was significantly greater than that of 5 (One way analysis of variance, Holm-Sidak method, †††p < 0.001 vs. 5 + CDDP group, α = 0.05). Co-pre-treating 5 with the sEHI bridged the gap in activity (One way analysis of variance, Holm-Sidak method, †††p < 0.001 vs. 5 + CDDP group, α = 0.05) and significantly shielded cells (One way analysis of variance, Holm-Sidak method, ***p < 0.001 vs. EtOH + CDDP group, α = 0.05). Finally, the cell protective effects of 2 and 3 were greater than that of 4 (One way analysis of variance, Holm-Sidak method, #p < 0.05 vs. 4 + CDDP group, α = 0.05).