FK866 plus bortezomib trigger synergistic inhibition of human MM cell growth in vivo. (A) Average and SD of tumor volume (mm3) from groups of mice (n = 7 per group) versus time (days) when tumor was measured. MM1S cells (5 × 106 in 100 µL of serum-free RPMI-1640 medium) were implanted in the flank of CB17 SCID mice. After tumor detection, mice were randomized to intraperitoneal treatment with vehicle, FK866, bortezomib, or their combination at the indicated doses over 3 weeks. A significant decrease in tumor growth was noted in combination-treated mice versus vehicle-treated mice (P = .0045 after the first week and P < .001 at the end of treatment). Data are mean tumor volume ± SD. Error bars represent mean ± SD. (B) Kaplan–Meier survival plot showing survival for mice treated with vehicle, FK866, bortezomib, or their combination at the indicated concentrations. FK866 plus bortezomib-treated mice show significantly increased survival (P = .007) in comparison with vehicle-treated mice. The mean overall survival was 20 days in the vehicle-treated cohort versus 37 days in the combination-treated cohort. (C) Micrographs show tumors sectioned on day 30 (endpoint) from vehicle-, FK866- (30 mg/kg), bortezomib- (0.5 mg/kg), or combination-treated mice immunostained for Ki-67, caspase 3, or CD31 expression. Photographs are representative of 2 mice receiving each treatment. (D) Cell lysates were prepared from tumor tissues harvested from treated and untreated mice and then analyzed by western blot analysis for Mcl-1 and Bcl-2 protein level.
