Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.
Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.
Ramer
Robert
R
Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.
Merkord
Jutta
J
Rohde
Helga
H
Hinz
Burkhard
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002185:Cannabidiol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D008175:Lung Neoplasms / Q000556:secondary; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness; D043882:Receptors, Cannabinoid / Q000502:physiology; D050916:TRPV Cation Channels / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D002185:Cannabidiol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9