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 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.
Yang
Peiying
P
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77090-1009, USA.
Collin
Peter
P
Madden
Timothy
T
Chan
Diana
D
Sweeney-Gotsch
Bridget
B
McConkey
David
D
Newman
Robert A
RA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D008855:Microscopy, Electron, Scanning; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D051381:Rats; D014407:Tumor Cells, Cultured
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D006131:Growth Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C069642:aseanostatin P5; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases