5-Lipoxygenase inhibitors induce potent anti-proliferative and cytotoxic effects in human tumour cells independently of suppression of 5-lipoxygenase activity.

Abstract

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.

• Authors: A S Fischer, J Metzner, S D Steinbrink, S Ulrich, C Angioni, G Geisslinger, D Steinhilber, T J Maier
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 161 Issue 4 Pg. 936-49 (Oct 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20860670 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Chemical References

• Antineoplastic Agents
• Lipoxygenase Inhibitors
• Arachidonate 5-Lipoxygenase
• Poly(ADP-ribose) Polymerases

Topics

• Antineoplastic Agents (pharmacology)
• Arachidonate 5-Lipoxygenase (drug effects, genetics, metabolism)
• Blotting, Western
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Lipoxygenase Inhibitors (pharmacology)
• Neoplasms (drug therapy, pathology)
• Poly(ADP-ribose) Polymerases (drug effects, metabolism)