Lung cancer is the leading cause of
cancer deaths worldwide. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and
tumor resistance. To target COX-2, 5-LOX, and ODC simultaneously, we tested the effects of a dual 5-LOX-COX inhibitor,
licofelone, and an ODC inhibitor, DFMO, alone and in combination, on NNK-induced lung
tumors in female A/J mice. Seven-week-old mice were treated with NNK (10 μmol/mouse, single dose, i.p.) and randomized to different treatment groups. Three weeks after injection, mice were fed control or experimental diets (DFMO 1500/3000 ppm,
licofelone 200/400 ppm, or a low-dose combination of 1500 ppm DFMO and 200 ppm
licofelone) for 17 or 34 weeks. Both agents significantly inhibited
tumor formation in a dose-dependent manner. As anticipated more
adenomas and
adenocarcinomas were observed
at 17 and 34 weeks, respectively. Importantly, low dose combination of DFMO and
licofelone showed more pronounced effects
at 17 or 34 weeks in inhibiting the total
tumor formation (~60%, p < 0.0001) and
adenocarcinoma (~65%, p < 0.0001) compared to individual high dose of DFMO (~44% and 46%, p < 0.0001) and
licofelone (~48% and 55%, p < 0.0001). DFMO and combination-treated mice lung
tumors exhibited modulated ODC pathway components (Oat, Oaz, SRM, SMS, and SAT, p < 0.05) along with decreased proliferation (
PCNA,
Cyclin D1 and
Cyclin A) and increased expression of p53, p21 and p27 compared to mice fed control diet. Both DFMO and
licofelone significantly inhibited
tumor inflammatory markers. Our findings suggest that a low-dose combined treatment targeting
inflammation and
polyamine synthesis may provide effective
chemoprevention.