Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines.
The omega-3 fatty acid ethanolamides, docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), displayed greater anti-proliferative potency than their parent omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in LNCaP and PC3 prostate cancer cells. DHEA and EPEA activated cannabinoid CB(1) and CB(2) receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB(1) and CB(2) receptors, and the CB(1)- and CB(2)-selective antagonists, AM281 and AM630, administered separately or together, reduced the anti-proliferative potencies of EPEA and EPA but not of DHEA or DHA in PC3 cells and of EPA but not of EPEA, DHEA or DHA in LNCaP cells. Even so, EPEA and EPA may not have inhibited PC3 or LNCaP cell proliferation via cannabinoid receptors since the anti-proliferative potency of EPEA was well below the potency it displayed as a CB(1) or CB(2) receptor agonist. Indeed, these receptors may mediate a protective effect because the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide-metabolizing enzyme, fatty acid amide hydrolase (FAAH), was highly expressed in LNCaP but not PC3 cells. Evidence was obtained that FAAH metabolizes EPEA and DHEA and that the anti-proliferative potencies of these ethanolamides in LNCaP cells can be enhanced by inhibiting this enzyme. Our findings suggest that the expression of cannabinoid receptors and of FAAH in some tumour cells could well influence the effectiveness of DHA and EPA or their ethanolamide derivatives as anticancer agents.
Brown
Iain
I
Cancer Medicine Research Programme, Translational Medical Sciences, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Polwarth Building, Aberdeen, AB25 2ZD, UK. i.brown@abdn.ac.uk
Cascio
Maria G
MG
Wahle
Klaus W J
KW
Smoum
Reem
R
Mechoulam
Raphael
R
Ross
Ruth A
RA
Pertwee
Roger G
RG
Heys
Steven D
SD
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000099252:Fatty Acid Amide Hydrolases
D000276:Adjuvants, Immunologic; D000581:Amidohydrolases; D003687:Dehydroepiandrosterone; D015525:Fatty Acids, Omega-3; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011944:Receptors, Androgen; D000099252:Fatty Acid Amide Hydrolases