Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1

FASEB J. 2012 Apr;26(4):1535-48. doi: 10.1096/fj.11-198184. Epub 2011 Dec 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cannabidiol / pharmacology
  • Cannabidiol / therapeutic use*
  • Female
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / pathology*
  • Neoplasm Transplantation
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Random Allocation
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects

Substances

  • RNA, Small Interfering
  • TRPV Cation Channels
  • TRPV1 receptor
  • Tissue Inhibitor of Metalloproteinase-1
  • Intercellular Adhesion Molecule-1
  • Cannabidiol
  • Mitogen-Activated Protein Kinases