Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines

Iain Brown (Corresponding Author), Maria G. Cascio, Klaus W. J. Wahle, Reem Smoum (Collaborator), Raphael Mechoulam, Ruth A. Ross, Roger G. Pertwee, Steven D. Heys

Research output: Contribution to journalArticle

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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 CB1 and CB2 receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB1 and CB2 receptors, and the CB1- and CB2-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 CB1 or CB2 receptor agonist. Indeed, these receptors may mediate a protective effect, since the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide catabolizing 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.
Original languageEnglish
Pages (from-to)1584-1591
Number of pages8
JournalCarcinogenesis
Volume31
Issue number9
Early online date25 Jul 2010
DOIs
Publication statusPublished - Sep 2010

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Cannabinoid Receptors
Androgen Receptors
Prostatic Neoplasms
Cell Line
Docosahexaenoic Acids
Cannabinoid Receptor CB2
Cannabinoid Receptor CB1
Eicosapentaenoic Acid
Omega-3 Fatty Acids
Endocannabinoids
Enzymes
Antineoplastic Agents
Cell Proliferation

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Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. / Brown, Iain (Corresponding Author); Cascio, Maria G.; Wahle, Klaus W. J.; Smoum, Reem (Collaborator); Mechoulam, Raphael; Ross, Ruth A.; Pertwee, Roger G.; Heys, Steven D.

In: Carcinogenesis, Vol. 31, No. 9, 09.2010, p. 1584-1591.

Research output: Contribution to journalArticle

Brown, Iain ; Cascio, Maria G. ; Wahle, Klaus W. J. ; Smoum, Reem ; Mechoulam, Raphael ; Ross, Ruth A. ; Pertwee, Roger G. ; Heys, Steven D. / Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. In: Carcinogenesis. 2010 ; Vol. 31, No. 9. pp. 1584-1591.
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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 CB1 and CB2 receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB1 and CB2 receptors, and the CB1- and CB2-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 CB1 or CB2 receptor agonist. Indeed, these receptors may mediate a protective effect, since the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide catabolizing 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.",
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AU - Cascio, Maria G.

AU - Wahle, Klaus W. J.

AU - Mechoulam, Raphael

AU - Ross, Ruth A.

AU - Pertwee, Roger G.

AU - Heys, Steven D.

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AB - 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 CB1 and CB2 receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB1 and CB2 receptors, and the CB1- and CB2-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 CB1 or CB2 receptor agonist. Indeed, these receptors may mediate a protective effect, since the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide catabolizing 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.

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DO - 10.1093/carcin/bgq151

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