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Biochem Biophys Res Commun. 2013 Nov 15;441(2):339-43. doi: 10.1016/j.bbrc.2013.10.057. Epub 2013 Oct 19.

CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen.

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


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.


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 receptor; G-protein coupled receptors; GPCR; IBMX; Inverse agonist; SERM; Tam; Tamoxifen; WIN-55,212-2; [(35)S]GTPγS; [(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

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