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Canna~Fangled Abstracts

CB1 and CB2 Receptors are Novel Molecular Targets for Tamoxifen and 4OH-Tamoxifen.

By October 24, 2013No Comments
[Epub ahead of print]

pm2CB1 and CB2 Receptors are Novel Molecular Targets for Tamoxifen and 4OH-Tamoxifen.

Source

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205, United States.

Abstract

Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9-3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs.
Copyright © 2013. Published by Elsevier Inc.

KEYWORDS:

4OH-Tam, 4OH-tamoxifen, 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol, AC, Antagonist, CB1R, CB2R, CHO, CP-55,940, Cannabinoid Receptors, Cannabinoids, Chinese hamster ovary, DMEM, Drug Action, Drug Discovery, Dulbecco’s Modification of Eagle’s Medium, ER, G-protein Coupled Receptors, G-protein coupled receptor, GPCR, IBMX, Inverse Agonist, SERM, Tam, WIN-55,212-2, [(35)S]GTPηS, [(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone, adenylyl cyclase, cannabinoid receptor type 1, cannabinoid receptor type 2, estrogen receptor, guanosine 5’-O-(3-[(35)S]thio)triphosphate, hCB2, hMOR, human CB2 receptors, human mu-opioid receptors, isobutyl-methyl-xanthine, selective estrogen receptor modulator, tamoxifen

PMID:

 

24148245

 

[PubMed – as supplied by publisher]
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