Anti-proliferative effect of a putative endocannabinoid, 2-arachidonylglyceryl ether in prostate carcinoma cells.

Abstract

Endocannabinoids (ECs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), inhibit proliferation of carcinoma cells. Several enzymes hydrolyze ECs to reduce endogenous EC concentrations and produce eicosanoids that promote cell growth. In this study, we determined the effects of EC hydrolysis inhibitors and a putative EC, 2-arachidonylglyceryl ether (noladin ether, NE) on proliferation of prostate carcinoma (PC-3, DU-145, and LNCaP) cells. PC-3 cells had the least specific hydrolysis activity for AEA and administration of AEA effectively inhibited cell proliferation. The proliferation inhibition was blocked by SR141716A (a selective CB1R antagonist) but not SR144528 (a selective CB2R antagonist), suggesting a CB1R-mediated inhibition mechanism. On the other hand, specific hydrolysis activity for 2-AG was high and 2-AG inhibited proliferation only in the presence of EC hydrolysis inhibitors. NE inhibited proliferation in a concentration-dependent manner; however, SR141716A, SR144528 and pertussis toxin did not block the NE-inhibited proliferation, suggesting a CBR-independent mechanism of NE. A peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662 did not block the NE-inhibited proliferation, suggesting that PPARγ was not involved. NE also induced cell cycle arrest in G(0)/G(1) phase in PC-3 cells. NE inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB p65) and down-regulated the expression of cyclin D1 and cyclin E in PC-3 cells, suggesting the NF-κB/cyclin D and cyclin E pathways are involved in the arrest of G1 cell cycle and inhibition of cell growth. These results indicate therapeutic potentials of EC hydrolysis inhibitors and the enzymatically stable NE in prostate cancer.

• Authors: Kasem Nithipatikom, Marilyn A Isbell, Michael P Endsley, Jeffrey E Woodliff, William B Campbell
• Journal: Prostaglandins & other lipid mediators (Prostaglandins Other Lipid Mediat) Vol. 94 Issue 1-2 Pg. 34-43 (Feb 2011) ISSN: 1098-8823 [Print] United States
• PMID: 21167293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• 2-chloro-5-nitrobenzanilide
• Anilides
• Antineoplastic Agents
• Cannabinoid Receptor Modulators
• Cyclin E
• Endocannabinoids
• Glycerides
• NF-kappa B
• PPAR gamma
• noladin ether
• Cyclin D1

Topics

• Anilides (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cannabinoid Receptor Modulators (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Cyclin D1 (metabolism)
• Cyclin E (metabolism)
• Endocannabinoids
• Glycerides (pharmacology)
• Humans
• Male
• NF-kappa B (metabolism)
• PPAR gamma (antagonists & inhibitors, metabolism)
• Prostate (pathology)
• Prostatic Neoplasms (metabolism, pathology)