Clinical and animal studies indicate a role for
cyclooxygenase-2 (COX-2) and the
epidermal growth factor receptor (EGFR) in the development and progression of
intestinal polyps and
cancers. Although this combination of
enzyme inhibition has shown synergy in
intestinal polyp and
tumor models, the exact mechanism for these effects remains undefined. Therefore, we sought to define the molecular mechanisms through which this process occurs. We observed a significant reduction in the number and size of small
intestinal polyps in APC(min+/-) mice treated with either
celecoxib (a selective
COX-2 inhibitor) or
erlotinib (
Tarceva, an EGFR inhibitor). However, in combination, there was an overall prevention in the formation of
polyps by over 96%. Furthermore, we observed a 70% reduction of colorectal xenograft
tumors in mice treated with the combination and microarray analysis revealed genes involved in cell cycle progression were negatively regulated. Although we did not observe significant changes in mRNAs of genes with known apoptotic function, there was a significant increase of apoptosis in
tumors from animals treated with the combination. The inhibition of EGFR also induced the down-regulation of COX-2 and further inhibited
prostaglandin E2 formation. We observed similar effects on the prevention of intestinal
adenomas and reduction of xenograft
tumor volume when nonselective COX inhibitors were used in combination with
erlotinib. Together, these findings suggest that the inhibition of both COX-2 and EGFR may provide a better therapeutic strategy than either single agent through a combination of decreased cellular proliferation and
prostaglandin signaling as well as increased apoptosis.