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. 2024 May 10;5(5):101558. doi: 10.1016/j.xcrm.2024.101558

Figure 7.

Figure 7

Inhibition of mevalonate metabolism induces myeloid differentiation and synergizes with MDM2i to induce apoptosis in AML cells

(A) Schematic representation of the mevalonate pathway. The mevalonate pathway, regulated by SREBP, is responsible for synthesizing cholesterol and isoprenoids. Statin drugs inhibit SREBP activation, affecting CoQ production and blocking Sqle-mediated cholesterol synthesis.

(B) Western blot analysis of Sqle, p53, p21, and b-actin levels in spleen cells derived from Vav-Cre;Mdm2+/+ and Vav-Cre;Mdm2+/fl, before and after irradiation (6 Gy). The figure displays bands corresponding to the molecular weights of the respective proteins.

(C) Quantification of p21 protein levels in (B), normalized to beta-actin. Bar graphs represent the mean protein expression level relative to the control, with error bars indicating the standard error of the mean (SEM) based on two separate blots.

(D) Western blot analysis of SREBP, Mdm2, p21, and β-actin protein levels in bone marrow cells derived from Vav-Cre;Mdm2+/+ and Vav-Cre;Mdm2+/fl, after irradiation (6 Gy). The bands at the corresponding molecular weights are displayed.

(E) Western blot analysis of K562 cells treated with indicated concentrations of XY018. The figure displays bands corresponding to the molecular weights of the respective proteins. The normalized levels of phospho-eIF2α are shown on the right.

(F) Quantification of myeloid cells (CD11b+) in CFU culture treated with atorvastatin, displaying means ± SDs. Each data point represents a measurement from an individual mouse. ∗∗∗∗p < 0.0001.

(G) Representative flow cytometry plot and quantification of the frequency of CD11b+ in HL60 cells after 48 h treatment with atorvastatin. ∗∗∗∗p < 0.0001.

(H) Percentage of live cells in indicated cells treated with different concentration of atorvastatin. Error bars indicate the standard error of the mean (SEM), representing the variability within the experimental replicates.

(I–K) Percentage of dead cells defined as Annexin V/DAPI(+) cells in indicated cell lines treated with indicated compounds and concentrations.

(L) Percentage of cells with high peroxidation index treated with indicated compounds.