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


METHODS
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.


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
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.
Fischer
A S
AS
Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt/Main, Germany.
Metzner
J
J
Steinbrink
S D
SD
Ulrich
S
S
Angioni
C
C
Geisslinger
G
G
Steinhilber
D
D
Maier
T J
TJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D011065:Poly(ADP-ribose) Polymerases