title: Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.
abstract: Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.
authors.affiliation: Institute of Toxicology and Pharmacology, Department of General Surgery, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ramer
authors.forename: Katharina
authors.initials: K
authors.lastname: Bublitz
authors.forename: Nadine
authors.initials: N
authors.lastname: Freimuth
authors.forename: Jutta
authors.initials: J
authors.lastname: Merkord
authors.forename: Helga
authors.initials: H
authors.lastname: Rohde
authors.forename: Maria
authors.initials: M
authors.lastname: Haustein
authors.forename: Philipp
authors.initials: P
authors.lastname: Borchert
authors.forename: Ellen
authors.initials: E
authors.lastname: Schmuhl
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000368:Aged; D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology*; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D019715:Tissue Inhibitor of Metalloproteinase-1; D018799:Intercellular Adhesion Molecule-1; D002185:Cannabidiol; D020928:Mitogen-Activated Protein Kinases