Despite the demonstrated benefits of anti-EGFR/
VEGF targeted
therapies in metastatic
colorectal cancer (mCRC), many patients initially respond, but then show evidence of
disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/
VEGF and
cyclooxygenase-2 (COX-2) may aid the treatment and management of mCRC patients. The dual
tyrosine kinase inhibitor AEE788 and
celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in
colorectal cancer cells. COX-2 inhibition with
celecoxib augmented the antitumoral and antiangiogenic efficacy of
AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down-regulation of
VEGF production by
cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined
AEE788/
celecoxib treatment prevented β-
catenin nuclear accumulation in
tumor cells. This effect was associated with a significant downregulation of
FOXM1 protein levels and an impairment in the interaction of this
transcription factor with β-
catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in
cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of
AEE788 and
celecoxib not only demonstrated enhanced anti-tumoral efficacy in
colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness-related pathways. Therefore, the simultaneous targeting of EGFR/
VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing
therapies in
colorectal cancer.