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Biochem Pharmacol. 2014 Nov 15;92(2):312-25. doi: 10.1016/j.bcp.2014.07.014. Epub 2014 Jul 25.

Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.

Author information

1
Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany.
2
Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany.
3
Department of Radiotherapy and Radiation Oncology, University of Rostock, Rostock, Germany.
4
Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany. Electronic address: burkhard.hinz@med.uni-rostock.de.

Abstract

Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 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 addition, enhanced killing of CBD-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated 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 Δ(9)-tetrahydrocannabinol (THC) and R(+)-methanandamide (MA), a hydrolysis-stable endocannabinoid analogue. Finally, each cannabinoid elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated 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.

KEYWORDS:

Cannabinoids; Immune surveillance; Intercellular adhesion molecule 1; Lung cancer; Lymphokine-activated killer cells

PMID:
25069049
DOI:
10.1016/j.bcp.2014.07.014
[Indexed for MEDLINE]

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