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Cannabinoids Increase Lung Cancer Cell Lysis By Lymphokine-​activated Killer Cells Via Upregulation Of Icam-​1


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 Biochemical Pharmacology (Amsterdam, Netherlands)

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DOI:10.1016/j.bcp.2014.07.014 Cannabinoids increase lung cancer cell lysis by lymphokine-​activated killer cells via upregulation of ICAM-​1

By: Haustein, Maria; Ramer, Robert; Linnebacher, Michael; Manda, Katrin; Hinz, Burkhard

Cannabinoids have been shown to promote the expression of the intercellular adhesion mol. 1 (ICAM-​1) on lung cancer cells as part of their anti-​invasive and antimetastatic action.  Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study addressed the impact of cannabinoid-​induced ICAM-​1 on cancer cell adhesion to lymphokine-​activated killer (LAK) cells and LAK cell-​mediated cytotoxicity.  Cannabidiol (CBD)​, a non-​psychoactive cannabinoid, enhanced the susceptibility of cancer cells to adhere to and subsequently be lysed by LAK cells, with both effects being reversed by a neutralizing ICAM-​1 antibody.  Increased cancer cell lysis by CBD was likewise abrogated when CBD-​induced ICAM-​1 expression was blocked by specific siRNA or by antagonists to cannabinoid receptors (CB1, CB2) and to transient receptor potential vanilloid 1.  In addn., enhanced killing of CBD-​treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function assocd. antigen-​1 (LFA-​1) suggesting intercellular ICAM-​1​/LFA-​1 crosslink as crucial event within this process.  ICAM-​1-​dependent pro-​killing effects were further confirmed for the phytocannabinoid Δ9-​tetrahydrocannabinol (THC) and R(+)​-​methanandamide (MA)​, a hydrolysis-​stable endocannabinoid analog.  Finally, each cannabinoid elicited no significant increase of LAK cell-​mediated lysis of non-​tumor bronchial epithelial cells, BEAS-​2B, assocd. with a far less pronounced (CBD, THC) or absent (MA) ICAM-​1 induction as compared to cancer cells.  Altogether, our data demonstrate cannabinoid-​induced upregulation of ICAM-​1 on lung cancer cells to be responsible for increased cancer cell lysis by LAK cells.  These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.

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