Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells.
OBJECTIVE
Using human lung cancer cells, we evaluated the involvement of plasminogen activator inhibitor-1 (PAI-1) in the anti-invasive action of cannabidiol, a non-psychoactive cannabinoid.


METHODS
Invasion was quantified by a modified Boyden chamber assay. PAI-1 protein in cell culture media and PAI-1 mRNA were determined by immunoblotting and RT-PCR, respectively.


RESULTS
Cannabidiol caused a profound inhibition of A549 cell invasion, accompanied by a decreased expression and secretion of PAI-1. Cannabidiol's effects on PAI-1 secretion and invasion were suppressed by antagonists to CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1. Recombinant human PAI-1 and PAI-1 siRNA led to a concentration-dependent up- and down-regulation of invasiveness, respectively, suggesting a crucial role of PAI-1 in A549 invasiveness. Evidence for a causal link between cannabidiol's effects on PAI-1 and invasion was provided by experiments showing a reversal of its anti-invasive action by addition of recombinant PAI-1 at non-proinvasive concentrations. Key data were confirmed in two other human lung cancer cell lines (H460, H358). In vivo, a significant downregulation of PAI-1 protein by cannabidiol was demonstrated in A549 xenografts.


CONCLUSIONS
Our data provide evidence for a hitherto unknown mechanism underlying the anti-invasive action of cannabidiol on human lung cancer cells.
Ramer
Robert
R
Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057, Rostock, Germany.
Rohde
Anja
A
Merkord
Jutta
J
Rohde
Helga
H
Hinz
Burkhard
B
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002185:Cannabidiol / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002185:Cannabidiol