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Issue Date: 6-May-2011
Authors: Scollo, Mimmo
Title: The antimitogenic effect of the cannabinoid receptor agonist WIN 55212-2 on human melanoma cells is mediated by the membrane lipid raft
Abstract: Melanoma is characterized by a poor prognosis. Therapeutic strategies for melanoma alternative to surgery are still under investigation, as all current treatments for this tumor appear scarcely efficient. In the light of these data, new strategies are required for the treatment of this disease. Cannabinoids have been shown to possess proapoptotic properties on different tumor cell types, and for this reason considered candidate molecules for innovative treatment of melanoma. In this work, the effects of the non selective cannabinoid receptors agonist WIN 55,212-2, have been studied on different human melanoma cell lines expressing CB1 and CB2 cannabinoid receptors. Interestingly, WIN induced a significant increase of cell death rate in melanoma cell cultures. Such effect did not appear mediated by either CB1or CB2 receptors. In fact, both the selective CB1 antagonist AM-251 and the selective CB2 antagonist AM-630, alone or in combination, were not able to protect melanoma cell lines by WIN-induced apoptosis. Similarly, both ACEA, a selective CB1 agonist and JWH-133, a selective CB2-R agonist, were not able to induce apoptosis in melanoma cells. Cannabinoids also interact with the Vanilloid Receptor 1(VR1) which is also expressed by various melanoma cell lines. However, SB366791, a potent, selective VR1 competitive antagonist, was not able to prevent WIN-induced apoptosis. Recently, other mechanisms have been hypothesized to explain WIN-55,212-dependent cell death, such as, for example, the pathway related to the membrane lipidic raft. In fact, methyl-à à ²-cyclodextrin, a membrane cholesterol depletor, partially prevented WIN-induced cell death associated with activation of caspases with the involvement of both the extrinsic and intrinsic apoptosis pathways. From the bulk of data, it appears plausible to hypothesize that along with multiple mechanisms underlying cannibinoid-mediated apoptosis, the pathways related with the lipid rafts are significantly involved in cannabinoid dependent melanomatous cell death. Finally, the lipid raft system could represent a novel molecular target for innovative treatment of melanoma.
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