Endocannabinoids New Targets for Drug Development

Marzo, Vincenzo Di; Bisogno, Tiziana; Petrocellis, Luciano De

doi:10.2174/1381612003399365

Cited by 62 publications

(47 citation statements)

References 147 publications

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“…1b). The chromatogram also contained small, more polar [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-radiolabeled peaks. One of these radioactive peaks comigrated with the 12-HETE standard (Fig.…”

Section: Metabolism Of 2-arachidonoylglycerol In Pc-3 Cellsmentioning

confidence: 99%

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Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Endsley¹,

Aggarwal²,

Isbell³

et al. 2007

Intl Journal of Cancer

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Endogenous 2‐arachidonoylglycerol (2‐AG) is antiinvasive in androgen‐independent prostate carcinoma (PC‐3) cells. Invasion of PC‐3 cells is also inhibited by exogenously added noladin ether, a non‐hydrolyzable analog of 2‐AG. In contrast, exogenous 2‐AG has the opposite effect. Cell invasion significantly increased with high concentrations of exogenous 2‐AG. In PC‐3 cells, arachidonic acid (AA) and 12‐hydroxyeicosatetraenoic acid (12‐HETE) concentrations increased along with exogenously added 2‐AG, and 12‐HETE concentrations increased with exogenously added AA. Invasion of PC‐3 cells also increased with exogenously added AA and 12(S)‐HETE but not 12(R)‐HETE. The exogenous 2‐AG‐induced invasion of PC‐3 cells was inhibited by 3‐octylthio‐1,1,1‐trifluoropropan‐2‐one (OTFP, an inhibitor of 2‐AG hydrolysis) and baicalein (a 12‐LO inhibitor). Western blot and RT‐PCR analyses indicated expression of 12‐HETE producing lipoxygenases (LOs), platelet‐type 12‐LO (P‐12‐LO) and leukocyte‐type 12‐LO (L‐12‐LO), in PC‐3 cells. These results suggest that exogenous 2‐AG induced, rather inhibited, cell invasion because of its rapid hydrolysis to free AA, and further metabolism by 12‐LO of AA to 12(S)‐HETE, a promoter of PC cell invasion. The results also suggest that PC‐3 cells and human prostate stromal (WPMY‐1) cells released free AA, 2‐AG, and 12‐HETE. In the microenvironment of the PC cells, this may contribute to the cell invasion. The 2‐AG hydrolysis and concentration of 2‐AG in microenvironment are critical for PC cell's fate. Therefore, inhibitors of 2‐AG hydrolysis could potentially serve as therapeutic agents for the treatment of prostate cancer. © 2007 Wiley‐Liss, Inc.

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Section: Metabolism Of 2-arachidonoylglycerol In Pc-3 Cellsmentioning

confidence: 99%

“…The endocannabinoid signaling system has recently been implicated in the regulation of various types of cancer. [3][4][5][6][7][8][9][10][11][12] However, the role of 2-AG in prostate carcinoma cells are not well understood. 2-AG inhibits prolactin-induced proliferation in DU-145 cells by activation of the CB 1 receptors.…”

mentioning

confidence: 99%

Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Endsley¹,

Aggarwal²,

Isbell³

et al. 2007

Intl Journal of Cancer

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“…Over the past few years, there has been a growing awareness that AEA and certain synthetic vanilloids exert CB 1 -and VR1-independent biological activities (Di Marzo et al, , 2000a. Thus, in CB1 ϩ/ϩ mice, the cannabimimetic effects of AEA are not affected by a selective CB 1 receptor antagonist (Adams et al, 1998), whereas in CB1 Ϫ/Ϫ mice AEA stimulates guanosine 5Ј-O-(3-thio)triphosphate binding in brain membranes (Di Marzo et al, 2000b), and arvanil induces inhibition of spasticity and pain via a VR1-independent pathway (Brooks et al, 2002).…”

mentioning

confidence: 99%

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

Sancho

Calzado²,

Marzo³

et al. 2003

Mol Pharmacol

123

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Anandamide (arachidonoylethanolamine, AEA), an endogenous agonist for both the cannabinoid CB 1 receptor and the vanilloid VR1 receptor, elicits neurobehavioral, anti-inflammatory, immunomodulatory, and proapoptotic effects. Because of the central role of nuclear factor-B (NF-B) in the inflammatory process and the immune response, we postulated that AEA might owe some of its effects to the suppression of NF-B. This study shows that AEA inhibits tumor necrosis factor-␣ (TNF␣)-induced NF-B activation by direct inhibition of the IB kinase (IKK)␤ and, to a lesser extent, the IKK␣ subunits of B inhibitor (IB) kinase complex, and that IKKs inhibition by AEA correlates with inhibition of IB␣ degradation, NF-B binding to DNA, and NF-B-dependent transcription in TNF␣-stimulated cells. AEA also prevents NF-B-dependent reporter gene expression induced by mitogen-activated protein kinase kinase kinase and NF-B-inducing kinase. The NF-B inhibitory activity of AEA was independent of CB 1 and CB 2 activation in TNF␣-stimulated 5.1 and A549 cell lines, which do not express vanilloid receptor 1, and was not mediated by hydrolytic products formed through the activity of the enzyme fatty acid amide hydrolase. Chemical modification markedly affected AEA inhibitory activity on NF-B, suggesting rather narrow structure-activity relationships and the specific interaction with a molecular target. Substitution of the alkyl moiety with less saturated fatty acids generally reduced or abolished activity. However, replacement of the ethanolamine "head" with a vanillyl group led to potent inhibition of TNF␣-induced NF-B-dependent transcription. These findings provide new mechanistic insights into the antiinflammatory and proapoptotic activities of AEA, and should foster the synthesis of improved analogs amenable to pharmaceutical development as anti-inflammatory agents.Endocannabinoids are a class of lipid mediators found in several tissues and structurally based on a polyunsaturated fatty acid amide or ester motifs . Anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglicerol (2-AG) are the main endocannabinoids described to date. They act as mediators in the brain and in peripheral tissues mainly through the stimulation of brain (CB 1 ) and peripheral (CB 2 ) cannabinoid receptors. Although AEA preferentially binds to CB 1 , 2-AG is equipotent at both receptor subtypes. AEA is produced by neurons and other cell types from the hydrolysis of the phospholipid precursor N-arachydonoylphosphatidylethanolamide, catalyzed by a Ca 2ϩ

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“…Recent studies have revealed a certain overlap among the binding sites for fatty acid derivatives of the cannabinoid CB 1 receptor (for review, see Pertwee, 1997), the vanilloid receptor type 1 (VR 1 ) for capsaicin (Caterina et al, 1997; for review, see Szallasi and Blumberg, 1999), and the membrane transporter for the endocannabinoid arachidonoylethanolamide (AEA; Devane et al, 1992; for review, see Di Marzo et al, 2000a). In particular, it was shown (Di Marzo et al, 1998) that some long-chain derivatives of capsaicin, such as olvanil (Dray, 1992), weakly bind to and activate the CB 1 receptor and competitively inhibit the AEA membrane transporter (AMT), whereas AEA was found to act as a full, albeit weak, agonist of VR 1 receptors (Zygmunt et al, 1999;Smart et al, 2000).…”

mentioning

confidence: 99%

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

Marzo¹,

Griffin²,

Petrocellis³

et al. 2002

J Pharmacol Exp Ther

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Arvanil, a structural "hybrid" between the endogenous cannabinoid CB 1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR 1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB 1 receptors, activate VR 1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB 1 receptor. Methylation of the amide group decreased the activity at VR 1 , AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR 1 and AMT, but not the affinity for CB 1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR 1 and AMT but exhibited little affinity for CB 1 receptors. The urea analog was a potent FAAH inhibitor (IC 50 ϭ 2.0 M). A water-soluble analog of arvanil, O-2142, was as active on VR 1 , much less active on AMT and CB 1 , and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC 50 Ͻ10 nM on VR 1 . However, the most potent compound, N-NЈ-di-(3-chloro-4-hydroxy)benzylarachidonamide (O-2093, ED 50 ϳ0.04 mg/kg), did not activate VR 1 or CB 1 receptors. Our findings suggest that VR 1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

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Endocannabinoids New Targets for Drug Development

Cited by 62 publications

References 147 publications

Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

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