title: The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi's sarcoma cells in vitro.
abstract: Kaposi's sarcoma is a highly vascularized mesenchymal neoplasm arising with multiple lesions of the skin. Endogenous cannabinoids have been shown to inhibit proliferation of a wide spectrum of tumor cells. We studied the effects of cannabinoids on human Kaposi's sarcoma cell proliferation in vitro. To do so, we first investigated the presence of the cannabinoid receptors CB(1) and CB(2) mRNAs in the human Kaposi's sarcoma cell line KS-IMM by RT-PCR and, subsequently, the effects of the mixed CB(1)/CB(2) agonist WIN-55,212-2 (WIN) on cell proliferation in vitro. WIN showed antimitogenic effects on Kaposi's sarcoma cells. Western blot analysis of Kaposi's sarcoma lysates suggested that WIN treatment induced activation of both caspase-3 and -6, as well as increased phosphorylation of the stress kinase p38 and JNK, along with transient phosphorylation of ERK(1/2). To better characterize the involvement of each single CB receptor in cannabinoid-induced cell death, we incubated Kaposi's sarcoma cells with different selective cannabinoid receptor agonists, respectively ACEA (CB(1)) and JWH-133 (CB(2)). None of the agonists was able to induce KS-IMM cell apoptosis. Moreover, we co-incubated Kaposi's sarcoma cells with WIN-55,212-2 and either the CB(1) receptor antagonist AM251, the CB(2) receptor antagonist AM630, or a combination of both substances. The CB(2) receptor antagonist AM630 was able to significantly increase survival of Kaposi's sarcoma cells treated with WIN. In view of the antiproliferative effects of cannabinoids on KS-IMM cells, one could envision the cannabinoid system as a potential target for pharmacological treatment of Kaposi's sarcoma.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Catania School of Medicine, 95125 Catania, Italy.
authors.forename: Tonia
authors.initials: T
authors.lastname: Luca
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Benedetto
authors.forename: Mariagrazia Rita
authors.initials: MR
authors.lastname: Scuderi
authors.forename: Marco
authors.initials: M
authors.lastname: Palumbo
authors.forename: Silvia
authors.initials: S
authors.lastname: Clementi
authors.forename: Renato
authors.initials: R
authors.lastname: Bernardini
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cantarella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D011247:Pregnancy; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases