Dual inhibition of COX-2/5-LOX blocks colon cancer proliferation, migration and invasion in vitro

Abstract

Inflammation is emerging as a new hallmark of cancer. Arachidonic acid (AA) metabolism, the family of cyclooxygenases (COXs) and lipoxygenase (LOX) play important roles in AA-related inflammatory cascades. In 94 colorectal cancer samples collected from the Han population, the immunohistochemical results indicated that 68% of the patients with colorectal cancer had a co-expression of both COX-2 and 5-LOX, while both displayed low expression in the matched normal tissues. In cell lines, three colorectal cancer cell lines exhibited high expression of COX-2 and 5-LOX. During stable silencing of the expression of COX-2 or 5-LOX in LoVo cancer cells, we found that downregulation of either COX-2 or 5-LOX significantly diminished the growth, migration and invasion of the colon cancer cells and specifically, downregulation of COX-2 could elicit upregulation of 5-LOX protein and vice versa. The above results suggested that the simultaneous blocking of COX-2 and 5-LOX activity may bring more potential benefits in managing the progression of colon cancer. Therefore, we sought to explore the effectiveness of a dual COX-2/5-LOX inhibitor darbufelone on the proliferation, migration, invasion and apoptosis of colon cancer cells, as well as the underlying mechanism of action. The results indicated that darbufelone significantly decreased the proliferative and invasive abilities of the colon cancer cells, in a dose-dependent manner. During the study of the related mechanisms, we found an upregulation of p27 and downregulation of cyclin D1 as well as CDK4 after darbufelone treatment, which indicated that darbufelone could arrest the cell cycle of LoVo cells at the G0/G1 phase. Furthermore, the activation of caspase-3 and -9, upregulation of Bax and downregulation of Bcl-2 demonstrated the occurrence of apoptosis by darbufelone. Finally, darbufelone also prevented the migration and invasion of LoVo cells, which may be ascribed to the upregulation of E-cadherin and ZO-1. In summary, our data suggest that the inhibition of both COX-2/5-LOX may be an effective therapeutic approach for colon cancer management, particularly for those patients with high expression of COX-2/5-LOX.

Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue

“…Some studies in CRC cell lines indicated that COX-2 inhibition results in an activation of the 5-lipoxygenase (LOX) pathway (49,50). At least in healthy colon tissue, our findings do not support this hypothesis, as 5-LOX-derived eicosanoid levels remained essentially unaffected upon ASA treatment.…”

Eicosanoids in carcinogenesis

“…It was suggested that Cox-2 is responsible for the regulation of the lipid metabolism [230]. This goes in line with the findings that inhibiting 5-LOX and Cox-2 blocks colon cancer proliferation, migration, as well as invasion in vitro [231]. This may explain why NSAID intake might result in some 50% reduction of the relative CRC risk [232,233] as the combined Cox-1 and Cox-2 activity is increased in CRC [234].…”

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

“…7) and 5-LOX is a key enzyme for leukotriene synthesis. This is of particular interest, as increased expression of 5-LOX promotes colon cancer cell proliferation in a direct manner 41,47 . However, more work is needed to determine how MC support colon cancer growth via 5-LOX.…”