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Decrease of Plasminogen Activator Inhibitor-1 May Contribute to the Anti-Invasive Action of Cannabidiol on Human Lung Cancer Cells

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ABSTRACT

Purpose

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 CB1 and CB2 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.

Conclusion

Our data provide evidence for a hitherto unknown mechanism underlying the anti-invasive action of cannabidiol on human lung cancer cells.

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Abbreviations

AM-251:

N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide

AM-630:

(6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl) (4-methoxyphenyl)methanone

CB1 :

cannabinoid receptor 1

CB2 :

cannabinoid receptor 2

RT-PCR:

reverse transcriptase-polymerase chain reaction

siRNA:

small-interfering RNA

TRPV1:

transient receptor potential vanilloid 1

WST-1:

4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1.6-benzene disulfonate

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ACKNOWLEDGEMENTS

This study was supported by grants from the Deutsche Krebshilfe e.V. (Bonn, Germany).

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Authors and Affiliations

  1. Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057, Rostock, Germany

    Robert Ramer, Anja Rohde, Jutta Merkord, Helga Rohde & Burkhard Hinz

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  1. Robert Ramer
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  2. Anja Rohde
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Correspondence to Burkhard Hinz.

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Ramer, R., Rohde, A., Merkord, J. et al. Decrease of Plasminogen Activator Inhibitor-1 May Contribute to the Anti-Invasive Action of Cannabidiol on Human Lung Cancer Cells. Pharm Res 27, 2162–2174 (2010). https://doi.org/10.1007/s11095-010-0219-2

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