The effect of cyclooxygenase-2 inhibition on arachidonic acid metabolism in cancer cell lines

B9

The observed over-expression of cyclooxygenase-2 (COX-2) in many types of cancer has highlighted this molecule as a potential target for therapeutic intervention. Also, it has been recently found that 5-lipoxygenase (5-LO) and cytochrome P450-2J2 (CYP2J2), another participants of arachidonic acid (AA) metabolism might have enough action to promote cancer cell viability through several mechanisms similar to those of COX-2. In head and neck squamous cell carcinoma (HNSCC) cell lines, we found that 5-LO is up-regulated as well as COX-2. Although COX-2 was highly expressed in all tested cell lines, several COX-2 inhibitory chemicals at low doses required to block COX-2 activity showed little growth inhibitory effect in our model. From these observations, we considered the possible interaction between COX-2 and 5-LO in AA metabolism to improve anti-cancer effect of COX-2 inhibition. Although low doses of NS-398 (~12.5uM) - COX-2 selective inhibitor and REV5901 (~6.25uM) - 5-LO inhibitor were enough to block synthesis of PGE2 and LTB4, they showed little cell growth inhibition of SNU-1041 individually. However, the combined treatment of NS-398 and REV5901 showed much better anti-cancer effect than any single application of them. We observed that COX-2 inhibition increased LTB4 produced by 5-lipoxygenase in all tested cells. From these findings, we assume that the combined inhibition of COX-2 and 5-LO related to AA metabolism should be necessary to overcome low efficacy of single inhibition of COX-2 and reduce the unexpected side effect by high doses of chemicals than it would be the optional modality in cancer cell with both expression of COX-2 and 5-LO. In another words, observation on expression of other factors related to AA pathway might be needed to optimize treatment efficiency of COX-2 inhibition in any cancer patients.