Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 161, Issue 4, Pages 936-949Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1476-5381.2010.00915.x
Keywords
leukotriene; apoptosis; cytotoxicity; off-target effect; zileuton; pancreatic cancer
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Funding
- German Graduate School 'Biologicals' [DFG GRK 1172]
- Merck KGaA, Darmstadt, Germany
- 'Landes Offensive zur Entwicklung Wissenschaftlich Okonomischer Exzellenz (LOEWE)/Lipid Signaling Forschungszentrum Frankfurt' (LiFF)
- German Excellence Cluster 'Cardio-Pulmonary System' (ECCPS)
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BACKGROUND AND PURPOSE Certain 5-lipoxygenase (5-LO) inhibitors exhibit anti-carcinogenic activities against 5-LO overexpressing tumour types and cultured tumour cells. It has been proposed therefore that 5-LO products significantly contribute to tumour cell proliferation. To date, the relationship between the inhibitory mechanisms of 5-LO inhibitors, which vary widely, and tumour cell viability has not been evaluated. This study addresses the anti-proliferative and cytotoxic potency of a number of 5-LO inhibitors with different inhibitory mechanisms in 5-LO-positive and 5-LO-negative tumour cells. EXPERIMENTAL APPROACH Cell viability was measured by the WST-1 assay; cell proliferation was assessed using the bromodeoxyuridine (BrdU) incorporation assay. Cell death was analysed by annexin V staining, Western blot analysis of PARP (poly ADP-ribose polymerase) cleavage and a cytotoxicity assay. 5-LO product formation was quantified by a 5-LO activity assay. KEY RESULTS The common 5-LO inhibitors AA-861, Rev-5901 and MK-886 induced cytotoxic and anti-proliferative effects in 5-LO-positive Capan-2 pancreatic cancer cells; BWA4C and CJ-13,610 only caused anti-proliferative effects, while zileuton failed to impair cell viability. Moreover, the concentrations of the 5-LO inhibitors required to induce anti-proliferation and cytotoxicity highly exceeded those for suppression of 5-LO. Supplementation with mitogenic 5-LO products failed to protect Capan-2 cells from the effects of 5-LO inhibitors. Finally, the cytotoxic and anti-proliferative 5-LO inhibitors also potently reduced the viability of 5-LO-deficient tumour cell lines (HeLa, Panc-1 and U937). CONCLUSIONS AND IMPLICATIONS Certain 5-LO inhibitors cause cytotoxic and anti-proliferative effects independently of suppression of 5-LO activity. Thus, the role of 5-LO overexpression in tumour cell viability remains unclear and requires further elucidation.
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