| 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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: N-arachidonyl-glycine modulates synaptic transmission in superficial dorsal horn.
Next Document: Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2.