Inhibition of proliferation of PC3 cells by the branched-chain fatty acid, 12-methyltetradecanoic acid, is associated with inhibition of 5-lipoxygenase.

Abstract

BACKGROUND:

Branched-chain fatty acids or fatty alcohols have been reported to possess anti-tumor activity in various tumor models. Here we study 12-methyltetradecanoic acid (12-MTA), a branched-chain fatty acid, isolated from a sea cucumber extract, on the growth of prostate cancer cells and investigate the underlying mechanisms of its effect.

METHODS:

12-MTA was evaluated by MTT assay for its ability to inhibit cell proliferation in various cancer types. The ability of 12-MTA to induce apoptosis of PC3 cells was examined by morphologic changes, propidium iodide (PI) staining, and caspase-3 activation. Furthermore, alteration of eicosanoid metabolism by 12-MTA was examined in PC3 and RBL-1 cells and in purified lipoxygenase (LOX) and cyclooxygenase (COX) enzymes.

RESULTS:

12-MTA inhibited proliferation of various cell lines, with IC50s ranging from 17.99 to 35.44 microg/ml. PI staining clearly showed that 12-MTA caused PC3 cell death through induction of apoptosis. At 50 microg/ml, 12-MTA increased caspase-3 activity four to seven-fold compared with that in control cells. Examination of cellular arachidonate metabolism showed that at 25 microg/ml, 12-MTA reduced the level of 5-hydroxyeicosatetraenoic acid (5-HETE) by 45%. Furthermore, exogenous 5-HETE protects PC3 cells from 12-MTA induced cell death.

CONCLUSIONS:

12-MTA inhibited proliferation of cancer cells via apoptosis, in which caspase-3 may play a role. At relevant concentrations, 12-MTA can selectively inhibit the formation of 5-HETE, a metabolite of 5-lipoxygenase. This agent may be a novel adjunctive therapy for selected malignancies including prostate cancer.

• Authors: Peiying Yang, Peter Collin, Timothy Madden, Diana Chan, Bridget Sweeney-Gotsch, David McConkey, Robert A Newman
• Journal: The Prostate (Prostate) Vol. 55 Issue 4 Pg. 281-91 (Jun 01 2003) ISSN: 0270-4137 [Print] United States
• PMID: 12712407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Cyclooxygenase Inhibitors
• Enzyme Inhibitors
• Fatty Acids
• Growth Inhibitors
• Hydroxyeicosatetraenoic Acids
• Lipoxygenase Inhibitors
• 5-hydroxy-6,8,11,14-eicosatetraenoic acid
• aseanostatin P5
• Arachidonate 5-Lipoxygenase
• Prostaglandin-Endoperoxide Synthases
• CASP3 protein, human
• Casp3 protein, rat
• Caspase 3
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Arachidonate 5-Lipoxygenase (metabolism)
• Caspase 3
• Caspases (metabolism)
• Cell Division (drug effects)
• Cyclooxygenase Inhibitors (pharmacology)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Fatty Acids (pharmacology)
• Female
• Flow Cytometry
• Growth Inhibitors (pharmacology)
• Humans
• Hydroxyeicosatetraenoic Acids (metabolism)
• Lipoxygenase Inhibitors
• Male
• Microscopy, Electron, Scanning
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Prostatic Neoplasms (drug therapy, enzymology)
• Rats
• Tumor Cells, Cultured