Luca Tonia, Di Benedetto Giulia, Scuderi Mariagrazia Rita, Palumbo Marco, Clementi Silvia, Bernardini Renato, Cantarella Giuseppina
Department of Experimental and Clinical Pharmacology, University of Catania School of Medicine, 95125 Catania, Italy.
Eur J Pharmacol. 2009 Aug 15;616(1-3):16-21. doi: 10.1016/j.ejphar.2009.06.004. Epub 2009 Jun 17.
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.
卡波西肉瘤是一种高度血管化的间充质肿瘤，表现为皮肤多发损害。内源性大麻素已被证明可抑制多种肿瘤细胞的增殖。我们研究了大麻素对人卡波西肉瘤细胞体外增殖的影响。为此，我们首先通过逆转录聚合酶链反应（RT-PCR）研究人卡波西肉瘤细胞系KS-IMM中大麻素受体CB(1)和CB(2) mRNA的存在情况，随后研究CB(1)/CB(2)混合激动剂WIN-55,212-2（WIN）对体外细胞增殖的影响。WIN对卡波西肉瘤细胞显示出抗有丝分裂作用。对卡波西肉瘤裂解物的蛋白质印迹分析表明，WIN处理可诱导半胱天冬酶-3和-6的激活，以及应激激酶p38和JNK磷酸化增加，同时伴有细胞外信号调节激酶(1/2)（ERK(1/2)）的短暂磷酸化。为了更好地描述每种单一CB受体在大麻素诱导的细胞死亡中的作用，我们分别用不同的选择性大麻素受体激动剂ACEA（CB(1)）和JWH-133（CB(2)）孵育人卡波西肉瘤细胞。这些激动剂均不能诱导KS-IMM细胞凋亡。此外，我们将人卡波西肉瘤细胞与WIN-55,212-2以及CB(1)受体拮抗剂AM251、CB(2)受体拮抗剂AM630或这两种物质的组合共同孵育。CB(2)受体拮抗剂AM630能够显著提高用WIN处理的卡波西肉瘤细胞的存活率。鉴于大麻素对KS-IMM细胞的抗增殖作用，可以设想大麻素系统是卡波西肉瘤药物治疗的潜在靶点。
