Inhibition of 5‐lipoxygenase pathway suppresses the growth of bladder cancer cells

Abstract

Aim: Many stimuli, including growth factors and cytokines, activate arachidonic acid (AA) metabolic pathways, which are involved in cancer development and progression. We examined the effects of a series of pharmacological inhibitors of AA metabolic enzymes on bladder cancer cells to determine the role of AA pathway in this malignancy. Methods: Human bladder cancer cell lines were treated with various AA metabolic enzymes inhibitors for lipoxygense (LOX) and cyclooxygenase (COX) pathways, and the growth suppression effects were examined. The enzyme expression in cancer cells was examined by immunoblot analyses. Results: A 5-LOX-specific inhibitor, AA861, dose-dependently inhibited the growth of bladder cancer cells. The growth inhibitory effects were greatly abolished by 5-LOX product, 5-HETE, but not by other LOX products examined. They were observed in four cancer cells that expressed 5-LOX, but not in one that did not. Of a series of LOX and COX pathway inhibitors, AA861 was the strongest one to suppress the growth of cancer cells. Conclusions: Bladder cancer cells frequently expressed 5-LOX. A 5-LOX-specific inhibitor, AA861, revealed the strongest growth suppression of those cells compared to other LOX and COX pathway inhibitors, and the growth suppression effects were considered to be due to inhibition of the enzymatic activity. Therefore, 5-LOX may play a regulatory role in proliferation and/or survival of bladder cancer, and may be a therapeutic target for the disease.

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…Additionally, 5-LOX inhibition affects epithelial-to-mesenchymal transition in certain cancer cell lines and suppresses metastasis in pancreatic cancer. These effects are likely due to the upregulation of E-cadherin and paxillin (58)(59)(60)(61). The finding that 12-LOX is overexpressed in murine lung carcinoma and human prostate cancer cells suggests a possible role for this enzyme in cancer development (22,62).…”

Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer

“…5-LOX expression also can be detected in dendritic cells, mast cells, and B-lymphocytes. LTs primarily mediate inflammatory and allergic reactions [28][29][30][31][32] by enhancing chemotaxis of migrating neutrophils and triggering vascular permeability and edema formation in inflamed tissues. Evidence also suggests a potential role of 5-LOX products in early stage pancreatic, prostate, and colorectal carcinogenesis [33][34][35][36][37].…”

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…. 5-HETE, one of 5-LOX important products, has direct proliferating activity on a subset of cancers [24] . To demonstrate whether 5-HETE contributes to the upregulation of FASN, we examined the effect of 5-HETE on FASN promoter activity.…”