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

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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 IC ranging from 17.99 to 35.44 μg/ml. PI staining clearly showed that 12‐MTA caused PC3 cell death through induction of apoptosis. At 50 μg/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 μg/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.