Journal: eLife
Article Title: A subset of CB002 xanthine analogs bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53
doi: 10.7554/eLife.70429
Figure Lengend Snippet: HCT116 isogenic panel treated with CB002 or analog #4 for 48 hr and their respective IC50 values shown in the table ( A ). CB002-analog #4 increases apoptotic cells as indicated by the sub-G1 content in cancer cells but not in normal WI38 cells (48 hr). Two-way ANOVA, p<0.0001 ( B ). 72 hr treatment with CB002-analog #4 is most potent ( C ) and increases dead cells as indicated by the ethidium homodimer staining (red) compared to calcein stained live cells (green) ( A ), and cleaved caspase-3 (green) immunofluorescence ( D ) in colorectal cancer patient-derived organoid cells. CB002-analog #4 decreases ki67 staining (green) in a dose-dependent manner (72 hr) in colorectal cancer patient-derived organoid cells ( E ). CB002-analog #4 is non-toxic in vivo ( F ) and significantly reduces tumor volume in NSG mouse xenografts with SW480 wild-type cells ( G ) but not in SW480 cells with shNoxa ( H ). 50 mg/kg by oral gavage three times per week, final tumor volume at 5 weeks. Unpaired t-test, p<0.05.
Article Snippet: DLD-1 (p53 S241F ) (RRID: CVCL_0248 ), SW480 (p53 R273H,P309S ) (RRID: CVCL_0546 ), and HCT116 (p53 WT ) (RRID: CVCL_0291 ) colorectal cancer cell lines and WI38 normal lung fibroblast cells were purchased from ATCC.
Techniques: Staining, Immunofluorescence, Derivative Assay, In Vivo