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

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 IC(50)s ranging from 17.99 to 35.44 mug/ml. PI staining clearly showed that 12-MTA caused PC3 cell death through induction of apoptosis. At 50 mug/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 mug/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. Prostate 55: 281-291, 2003. (C) 2003 Wiley-Liss, Inc.