TABLE 2.
The inhibition of NAMPT by FK866 led to attenuation of HCT116 tumor growth and alteration of tumor glycolytic and pentose phosphate pathway metabolite levels
Tumor xenografts derived from HCT116 were grown and treated with FK866 and processed for the analysis of metabolites by LC-MS as described (“Experimental Procedures”). NA, nicotinic acid; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; FBP, fructose 1,6-bisphosphate; G3P, glyceraldehydes 3-phosphate; DHAP, dihydroxyacetone phosphate; 2(3)PG, 2-phosphoglycerate and 3-phosphoglycerate; PEP, phosphoenolpyruvate; R5P, ribose 5-phosphate, ribulose 5-phosphate, and xylulose 5-phosphate; Gn6P, 6-phosphogluconate; and S7P, sedoheptulose 7-phosphate.
| Treatment groupsa |
||||||||
|---|---|---|---|---|---|---|---|---|
| FK (0.0) | FK (8.0) | FK (15.0) | FK (20.0) | FK (0.0) + NA | FK (8.0) + NA | FK(15.0) + NA | FK (20.0) + NA | |
| Tumor growth inhibition (%)b | 0.0 ± 13 | 40.3 ± 8.3 | 64 ± 3.7 | 64.2 ± 6.9 | 0.0 ± 9.7 | −4 ± 9.1 | 13 ± 8.9 | −4 ± 9.4 |
| Metabolite levels (ng/mg)c | ||||||||
| G6P and F6P | 9.9 ± 1.5 | 121 ± 16 | 84 ± 13 | 124 ± 22 | 15.2 ± 4.2 | 8.7 ± 1.7 | 13.9 ± 3.4 | 14.6 ± 2.6 |
| FBP | 81 ± 12.6 | 1114 ± 140 | 636 ± 115 | 719 ± 238 | 96 ± 25 | 68 ± 8 | 101 ± 22 | 77 ± 14 |
| G3P and DHAP | 0.3 ± 0.1 | 14.8 ± 2.6 | 5.9 ± 1 | 8.4 ± 2.3 | 0.5 ± 0.2 | 0.04 ± 0.0 | 0.1 ± 0.03 | 0.4 ± 0.3 |
| 2(3)PG | 53 ± 5.3 | 89 ± 8.6 | 41 ± 8.5 | 63 ± 18.8 | 45 ± 6 | 50 ± 9.7 | 44 ± 5.9 | 78 ± 11.1 |
| PEP | 4.4 ± 0.4 | 4.7 ± 0.4 | 2.5 ± 0.5 | 3.2 ± 0.9 | 3.4 ± 0.2 | 3.7 ± 0.5 | 3.5 ± 0.2 | 5.3 ± 0.9 |
| R5P | 16.7 ± 2 | 32.1 ± 4.3 | 21.4 ± 5.2 | 22 ± 3.9 | 18.8 ± 1.8 | 19.5 ± 1.2 | 14 ± 1.7 | 24 ± 2.4 |
| Gn6P | 7.3 ± 1.5 | 16.5 ± 5 | 6.8 ± 1.7 | 5.9 ± 1.5 | 6.6 ± 1.0 | 2.9 ± 0.4 | 4.7 ± 0.7 | 3.2 ± 0.7 |
| S7P | 18 ± 4.6 | 208 ± 31.6 | 100 ± 17.8 | 104 ± 28.3 | 27 ± 4.2 | 21 ± 2.5 | 25 ± 5.5 | 27 ± 4.7 |
| NAD+ | 63 ± 43 | 4.2 ± 4.4 | 3.9 ± 4.9 | 3.7 ± 5.3 | 31 ± 19.7 | 40 ± 15 | 36 ± 17 | 19 ± 10.6 |
a Treatment groups: FK (0.0) = FK866 (0.0 mg/kg), FK (8.0) = FK866 (8.0 mg/kg), FK (15.0) = FK866 (15.0 mg/kg), FK (20.0) = FK866 (20.0 mg/kg), FK (0.0) + NA = FK866 (0.0 mg/kg) + nicotinic acid (75 mg/kg), FK (8.0) + NA = FK866 (8.0 mg/kg) + nicotinic acid (75 mg/kg), FK(15.0) + NA = FK866 (15.0 mg/kg) + nicotinic acid (75 mg/kg), and FK (20.0) + NA = FK866 (20.0 mg/kg) + nicotinic acid (75 mg/kg).
b Tumor grow inhibition (means ± S.E. of the mean) was calculated at the end of the study when compared to the vehicle (untreated) control groups.
c Tumor metabolite levels (means ± S.E. of the mean).