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5‐Lipoxygenase inhibitors induce potent anti‐proliferative and cytotoxic effects in human tumour cells independently of suppression of 5‐lipoxygenase activity
Author(s) -
Fischer AS,
Metzner J,
Steinbrink SD,
Ulrich S,
Angioni C,
Geisslinger G,
Steinhilber D,
Maier TJ
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00915.x
Subject(s) - cytotoxic t cell , cytotoxicity , viability assay , cell growth , microbiology and biotechnology , cell culture , arachidonate 5 lipoxygenase , chemistry , cell cycle , hela , biology , mtt assay , cancer research , apoptosis , cell , in vitro , biochemistry , enzyme , genetics , arachidonic acid
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.