Abstract
Lipoxygenases (LOXs) have been implicated in carcinogenesis in various cancer types.
In the current study, three structurally different lichen metabolites, protolichesterinic
acid (1), lobaric acid (2) and baeomycesic acid (3) were tested for anti-proliferative effects against 12 different human cancer cell
lines. All compounds have known in vitro 5-LOX inhibitory activity, and 1 and 2 also inhibit 12-LOX. The activity of the lichen metabolites was compared to that
of a specific 5-LOX inhibitor, zileuton (4). The following cancer cell lines were tested: Capan-1, Capan-2 and PANC-1 (all from
pancreas), T47-D (breast), PC-3 (prostate), NCI-H1417 (small cell lung), NIH:OVCAR-3
(ovary), AGS (stomach), WiDr (colorectal), HL-60, K-562 and JURKAT (acute promyelocytic,
erythro- and T-cell leukemia, respectively). Compound 1 showed the greatest inhibitory effect against all cell lines, with EC50 ranging from 2.4 - 18.1 μg mL-1 (7.4 - 55.8 μM), followed by 2, with EC50 of 15.2 - 65.5 μg mL-1 (33.2 - 143.6 μM). The effects of 3 and 4 were of similar orders of magnitude, with EC50 of 28.7 - >80 μg mL-1 (76.8 - > 213.9 μM) and 12.9 - > 80 μg mL-1 (50.4 - > 313.7 μM). The dual 5- and 12-LOX inhibitors 1 and to some extent 2 thus exert significant anti-proliferative effects against a variety of human cancer
cell lines, while the selective 5-LOX inhibitors 3 and 4 are considerably less active.
References
- 1
Ingólfsdóttir K, Breu W, Huneck S, Gudjónsdóttir G A, Müller-Jakic B, Wagner H.
In vitro inhibition of 5-lipoxygenase by protolichesterinic acid from Cetraria islandica
.
Phytomedicine.
1994;
1
187-91
- 2
Ingólfsdóttir K, Gissurarson S R, Müller-Jakic B, Breu W, Wagner H.
Inhibitory effects of the lichen metabolite lobaric acid on arachidonate metabolism
in vitro
.
Phytomedicine.
1996;
2
243-6
- 3
Ingólfsdóttir K, Birgisdóttir M, Wiedermann B, Nenninger A, Jónsdóttir S, Wagner H.
Inhibitory effects of baeomycesic acid from Thamnolia subuliformis on arachidonate metabolism.
Phytomedicine.
1997;
4
125-8
- 4 Bucar F, Schneider I, Ögmundsdóttir H, Ingólfsdóttir K. Anti-proliferative lichen
compounds with inhibitory activity on 12(S)-HETE production in human platelets. Phytomedicine 2004: in press
- 5
Ghosh J, Myers C E.
Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase.
Biochem Biophys Res Commun.
1997;
235
418-23
- 6
Ding X Z, Iversen P, Cluck M W, Knezetic J A, Adrian T E.
Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells.
Biochem Biophys Res Commun..
1999;
261
218-23
- 7
Rioux N, Castonguay A.
Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents.
Carcinogenesis.
1998;
19
1393-400
- 8
Tong W G, Ding X Z, Adrian T E.
The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer
cells.
Biochem Biophys Acta.
2002;
296
942-8
- 9
Ögmundsdóttir H M, Zoëga G M, Gissurarson S R, Ingólfsdóttir K.
Anti-proliferative effects of lichen-derived inhibitors of 5-lipoxygenase on malignant
cell lines and mitogen-stimulated lymphocytes.
J Pharm Pharmacol.
1998;
50
107-15
- 10
Carter G W, Young P R, Albert D H, Bouska J, Dyer R, Bell R L. et al .
5-Lipoxygenase inhibitory activity of zileuton.
J Pharmacol Exp Ther.
1991;
256
929-37
- 11
Hussey H J, Tisdale M J.
Inhibition of tumour growth by lipoxygenase inhibitors.
Br J Cancer.
1996;
74
683-7
- 12 Cordell G A, Kinghorn D, Pezzuto J M. Separation, structure elucidation and bioassay
of cytotoxic natural products. In: Molyneux RJ, editor
Bioactive natural products. Boca Raton; CRC Press 1993: pp 195-216
Helga M. Ögmundsdóttir
Faculty of Medicine
Vatnsmyrarvegi 16
101 Reykjavik
Iceland
Telefon: +354-525-4897
Fax: +354-525-4884
eMail: helgaogm@hi.is