Fig. 4: Combination of radiation and Mdm2 inhibitor (Mdm2i) sustains p53 activity in tissues and tumors resulting in reduced tumor progression.
From: p53 dynamics vary between tissues and are linked with radiation sensitivity
a Staining of p53 in the small intestine 5 h following the indicated treatments. Mdm2i was added 2 h after radiation (IR). Representative images from two independent experiments are shown. b p53 transcriptional activity in small intestine and spleen as measured by Mdm2 mRNA levels at the indicated time-points following treatment with Mdm2i. (n = 3 mice; error bars are SEM; *pval = 0.0071; two-sided t-test). c–e Representative images of staining for p53 (c), p53-phosphoS15 (d), and p53 target gene p21 (e) in the small intestines treated with IR alone or IR + Mdm2i as described in a. n = 3 mice, 15 crypts/mouse, *indicates significant, pval = 1.7 × 10−21 (c), 6.4 × 10−9 (d), and 5 × 10−5 (e) (two-sided t-test). f HCT116 tumors were engrafted for 21 days to an average size of 70 mm3 and then treated with radiation followed by vehicle or Mdm2i 2 h post radiation. Tumors were stained for p53 5 h after radiation treatment. Experiment was performed on 3–4 tumors/condition. g Quantification of data from f (n = 3–4 tumors per condition; dots indicate individual measurements; error bars are SEM; *pval = 0.0053; two-sided t-test). h Tumor sizes at the indicated time points in mice treated with or without radiation and then treated with or without Mdm2i 2 h post radiation (error bars are SEM). i Final tumor sizes from data in h. (* indicates significant, 0.0096, 0.0130, 0.0261; one-sided t-test). Dots represent individual tumors (n = 7–14 tumors/condition; error bars are SEM). No multiple test correction was used on the statistics in this figure.
