A new strategy to block tumor growth by inhibiting endocannabinoid inactivation

Bifulco, Maurizio; Laezza, Chiara; Valenti, Marta; Ligresti, Alessia; Portella, Giuseppe; Marzo, Vincenzo Di

doi:10.1096/fj.04-1754fje

Cited by 146 publications

(121 citation statements)

References 30 publications

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“…The present report suggests that such compensatory signaling can be positively modulated through the inhibition of endocannabinoid transport and hydrolysis with the AM374/ AM404 drug combination. Previous reports have described various types of beneficial effects by individually inhibiting the transport activity (Lastres-Becker et al, 2002;Marsicano et al, 2003;Bifulco et al, 2004;Fernandez-Espejo et al, 2004;Mestre et al, 2005) or FAAH (Maccarrone et al, 2003;Bifulco et al, 2004). In vitro and in vivo models were used here to show that dual modulation of the endocannabinoid system protects against cellular and functional consequences ascribed to excitotoxic events, such as stroke and traumatic brain injury.…”

Section: Discussionmentioning

confidence: 98%

“…The growing list includes potential treatments for chemotherapy complications (Sharma et al, 2005), tumor growth (Bifulco et al, 2004), pain (Calignano et al, 1998), Parkinson's disease (Maccarrone et al, 2003;FernandezEspejo et al, 2004), Huntington's disease (Lastres-Becker et al, 2002), Alzheimer's disease (Ramirez et al, 2005), multiple sclerosis (Mestre et al, 2005), amyotrophic lateral sclerosis (Raman et al, 2004), glaucoma (El-Remessy et al, 2003), as well as traumatic brain injury (Panikashvili et al, 2001), cerebral ischemia (Nagayama et al, 1999), and other excitotoxic insults (Shen and Thayer, 1998;Marsicano et al, 2003). The protective effects may involve signal transduction pathways linked to cannabinoid CB 1 receptors that recognize the endocannabinoids anandamide and 2-arachidonylglycerol (Bouaboula et al, 1995;Derkinderen et al, 1998Derkinderen et al, , 2003Galve-Roperh et al, 2002;Karanian et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

112

109

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The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB 1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB 1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB 1 agonist AM356 (R-methanandamide). AM374/ AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB 1 -linked MAPK signaling, and (3) were blocked by a selective CB 1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB 1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

112

109

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show abstract

“…Increasing evidence suggests that cannabinoids exert both direct and indirect effects on cancer by different mechanisms of action in different types of malignancies [5,6]. Cannabinoids have been found to control cell growth and death in many cancer types, both in vitro and in vivo [7][8][9], as well as the neoangiogenesis and metastatic spreading calcium, drop in mitochondrial membrane potential, release of cytochrome c and activation of caspases.…”

Section: Introductionmentioning

confidence: 99%

Rimonabant-induced apoptosis in leukemia cell lines: Activation of caspase-dependent and -independent pathways

Gallotta¹,

Nigro²,

Cotugno³

et al. 2010

Biochemical Pharmacology

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Rimonabant (SR141716), a cannabinoid CB1 receptor antagonist known for anti-obesity activity, has more recently been shown to inhibit tumor cell growth. Here we demonstrated the anti-tumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716(1-20 M range of doses) reduced Jurkat and U937 cell number by activating death signals as well as affecting cell cycle progression. The most prominent response in U937 to SR141716 was a G 0 /G 1 block, while in Jurkat cells there was activation of cell death processes.SR141716-treated cells exhibited the morphological and biochemical features of apoptosis and to some extent necrosis. Apoptotic mode of cell death was confirmed in both cell lines by analysis of cell morphology, phosphatidylserine exposure and DNA fragmentation. Moreover, the drug was found to induce an early and robust mitochondrial membrane depolarization. In Jurkat cells the apoptotic process was typically caspase-dependent, while in U937 caspase-independent pathways were also activated. The contribution of PARP activation to SR141716-induced apoptosis in U937 was suggested by protein PARylation, AIF release and apoptosis reversal by PARP inhibitors.Moreover, SR141716 negatively modulated, especially in U937, the PI3K/AKT pathways. In conclusion, our data indicate that SR141716 elicits alternative response and/or cell death pathways depending on the cell type affected.

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“…Whereas fewer studies have looked into cannabinoid and rimonabant effects in other types of cancer, rimonabantsensitive inhibitory effects of cannabinoids on tumor cell growth were reported for thyroid (Bifulco et al 2001(Bifulco et al , 2004 and liver cancer (Upham et al 2003). On the other hand, rimonabant was found to have additive inhibitory effects with anandamide on mantle cell lymphoma (Flygare et al 2005) and not to affect cannabinoid-induced growth inhibition in C6 glioma cells (Jacobsson et al 2001;Sanchez et al 1998Sanchez et al , 2001.…”

Section: Cancermentioning

confidence: 99%

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

Diepen

Schlicker

Michel

2008

Naunyn-Schmied Arch Pharmacol

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Rimonabant is an inverse agonist specific for cannabinoid receptors and selective for their cannabinoid-1 (CB 1 ) subtype. Although CB 1 receptors are more abundant in the central nervous system, rimonabant has many effects in the periphery, most of which are related to prejunctional modulation of transmitter release from autonomic nerves. However, CB 1 receptors are also expressed in, e.g., adipocytes and endothelial cells. Rimonabant inhibits numerous cardiovascular cannabinoid effects, including the decrease of blood pressure by central and peripheral (cardiac and vascular) sites of action, with the latter often being endothelium dependent. Rimonabant may also antagonize cannabinoid effects in myocardial infarction and in hypotension associated with septic shock or liver cirrhosis. In the gastrointestinal tract, rimonabant counteracts the cannabinoid-induced inhibition of secretion and motility. Although not affecting most cannabinoid effects in the airways, rimonabant counteracts inhibition of smoothmuscle contraction by cannabinoids in urogenital tissues and may interfere with embryo attachment and outgrowth of blastocysts. It inhibits cannabinoid-induced decreases of intraocular pressure. Rimonabant can inhibit proliferation of, maturation of, and energy storage by adipocytes. Among the many cannabinoid effects on hormone secretion, only some are rimonabant sensitive. The effects of rimonabant on the immune system are not fully clear, and it may inhibit or stimulate proliferation in several types of cancer. We conclude that direct effects of rimonabant on adipocytes may contribute to its clinical role in treating obesity. Other peripheral effects, many of which occur prejunctionally, may also contribute to its overall clinical profile and lead to additional indications as well adverse events.

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A new strategy to block tumor growth by inhibiting endocannabinoid inactivation

Cited by 146 publications

References 30 publications

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Rimonabant-induced apoptosis in leukemia cell lines: Activation of caspase-dependent and -independent pathways

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

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