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Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

      Summary

      Background

      Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation.

      Objective

      We investigated the plant cannabinoids Δ-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors.

      Methods

      A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors.

      Results

      The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either CB1/CB2 antagonists.

      Conclusion

      The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.

      Abbreviations:

      CBG (cannabigerol), CBD (cannabidiol), THC (tetrahydrocannabinol), CB (cannabinoid)

      Keywords

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      References

        • Bowcock A.M.
        • Krueger J.G.
        Getting under the skin: the immunogenetics of psoriasis.
        Nat Rev Immunol. 2005; 5 (review. Erratum in: Nat Rev Immunol 2005 October;5(10):826): 699-711
        • Krueger J.G.
        • Bowcock A.
        Psoriasis pathophysiology: current concepts of pathogenesis.
        Ann Rheum Dis. 2005; 64 (review): ii30-ii36
        • Klein T.W.
        Cannabinoid-based drugs as anti-inflammatory therapeutics.
        Nat Rev Immunol. 2005; 5 (review): 400-411
        • Kogan N.W.
        Cannabinoids and cancer.
        Mini Rev Med Chem. 2005; 5 (review): 941-952
        • Klein T.W.
        • Newton C.
        • Larsen K.
        • Lu L.
        • Perkins I.
        • Nong L.
        • et al.
        The cannabinoid system and immune modulation.
        J Leukoc Biol. 2003; 74 (Epub July 1, 2003, review): 486-496
        • Klein T.W.
        • Newton C.
        • Larsen K.
        • Chou J.
        • Perkins I.
        • Lu L.
        • et al.
        Cannabinoid receptors and T helper cells.
        J Neuroimmunol. 2004; 147: 91-94
        • Casanova M.L.
        • Blazquez C.
        • Martinez-Palacio J.
        • Villanueva C.
        • Fernandez-Acenero M.J.
        • Huffman J.W.
        • et al.
        Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.
        J Clin Invest. 2003; 111: 43-50
        • Maccarrone M.
        • Di Rienzo M.
        • Battista N.
        • Gasperi V.
        • Guerrieri P.
        • Rossi A.
        • et al.
        The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase.
        J Biol Chem. 2003; 278: 33896-33903
        • Mechoulam R.
        • Parker L.A.
        • Gallily R.
        Cannabidiol: an overview of some pharmacological aspects.
        J Clin Pharmacol. 2002; 42 (review): 11S-19S
        • Skehan P.
        • Storeng R.
        • Scudiero D.
        • et al.
        New colorimetric cytotoxicity assay for anticancer-drug screening.
        J Natl Cancer Inst. 1990; 82: 1107-1112
        • Racher A.
        Doyle A. Griffiths J. Laboratory procedures in biotechnology. John Wiley & Sons, NY1998
        • Stanely P.E.
        • Williams S.G.
        Use of the liquid scintillation spectrometer for determining adenosine triphosphate by the luciferase enzyme.
        Anal Biochem. 1969; 29: 381-392
        • Hayakawa K.
        • Mishima K.
        • Abe K.
        • et al.
        Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism.
        Neuroreport. 2004; 15: 2381-2385
        • Vaccani A.
        • Massi P.
        • Colombo A.
        • Rubino T.
        • Parolaro D.
        Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism.
        Br J Pharmacol. 2005; 144: 1032-1036
      1. Baker D, Pryce G, Davies WL, Hiley CR. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 2005 November 27.

        • Burstein S.
        PPAR-gamma: a nuclear receptor with affinity for cannabinoids.
        Life Sci. 2005; 77 (review): 1674-1684
        • Kuenzli S.
        • Saurat J.H.
        Peroxisome proliferator-activated receptors as new molecular targets in psoriasis.
        Curr Drug Targets Inflamm Allergy. 2004; 3 (review): 205-211
        • Bhagavathula N.
        • Nerusu K.C.
        • Lal A.
        • et al.
        Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes.
        J Invest Dermatol. 2004; 122: 130-139
        • Ellis C.N.
        • Varani J.
        • Fisher G.J.
        • Zeigler M.E.
        • Pershadsingh H.A.
        • Benson S.C.
        • et al.
        Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.
        Arch Dermatol. 2000; 136: 609-616