1. Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines.
- Author
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Brown I, Cascio MG, Wahle KW, Smoum R, Mechoulam R, Ross RA, Pertwee RG, and Heys SD
- Subjects
- Adjuvants, Immunologic pharmacology, Amidohydrolases genetics, Amidohydrolases metabolism, Animals, Apoptosis drug effects, Blotting, Western, CHO Cells, Cell Cycle drug effects, Cell Membrane metabolism, Cricetinae, Cricetulus, Dehydroepiandrosterone pharmacology, Flow Cytometry, Humans, Male, Mice, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, RNA, Messenger genetics, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 genetics, Receptor, Cannabinoid, CB2 antagonists & inhibitors, Receptor, Cannabinoid, CB2 genetics, Receptors, Androgen genetics, Receptors, Androgen metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Cell Proliferation drug effects, Fatty Acids, Omega-3 pharmacology, Prostatic Neoplasms drug therapy, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism
- Abstract
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.
- Published
- 2010
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