Document Detail


5-Lipoxygenase inhibitors induce potent anti-proliferative and cytotoxic effects in human tumour cells independently of suppression of 5-lipoxygenase activity.
MedLine Citation:
PMID:  20860670     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  161     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-23     Completed Date:  2010-12-02     Revised Date:  2012-04-27    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  936-49     Citation Subset:  IM    
Copyright Information:
© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.
Affiliation:
Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt/Main, Germany.
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MeSH Terms
Descriptor/Qualifier:
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
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Lipoxygenase Inhibitors; EC 1.13.11.34/Arachidonate 5-Lipoxygenase; EC 2.4.2.30/Poly(ADP-ribose) Polymerases
Comments/Corrections

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