Figure 6. MLN4924 radiosensitization in MiaPaCa-2 in vivo xenograft tumor model.

(A) MLN4924 inhibits cullin-1 neddylation and causes accumulation of SCF E3 substrates in tumor tissues: In this biomarker experiment, 5×10⁶ MiaPaCa-2 cells were inoculated s.c in both flank sides (R, right; L, left) of nude mice. The mice were randomized when the tumor size reached 100 mm³ at 14 days after inoculation and were treated with single dose of HPBCD (vehicle control) or with MLN4924, radiation, or MLN4924-radiation combination, as indicated. Tumor tissues (n=2 per group) were harvested at indicated time points for IB. (B &C) In vivo radiosensitizing activity of MLN4924 in the MiaPaCa-2 xenograft model: The tumor inoculation and animal randomization were as described above. The number of tumors for each group are as follows: Control (HPBCD), n=12, radiation (1 Gy), n=12, MLN4924 (30 mg/kg, s.c, once a day for 5 day/week for 3 weeks), n=16, or combination (MLN4924 was given 2–3 hrs prior to radiation), n=16. The tumor growth was monitored up to 65 days and growth curve plotted. The arrow indicates the treatment end time. Student’s t test was used to compare each treatment group with the control group. Shown are mean ± SEM, * indicates p<0.05 (B), and average time periods required for tumors to double or triple in size (C). (D). MLN4924 is well tolerated by mice: Body weight was measured during the treatment and plotted (mean ± SEM).