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Research ArticleCELLULAR AND MOLECULAR

Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Paola Massi, Angelo Vaccani, Stefania Ceruti, Arianna Colombo, Maria P. Abbracchio and Daniela Parolaro
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 838-845; DOI: https://doi.org/10.1124/jpet.103.061002
Paola Massi
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Angelo Vaccani
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Stefania Ceruti
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Arianna Colombo
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Maria P. Abbracchio
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Daniela Parolaro
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Abstract

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC50 of 25 μM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and α-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

Footnotes

  • This work was supported by a grant from the Cannabinoid Research Institute, affiliated with GW Pharmaceuticals, Oxford, UK, and by a grant from the Italian Ministry for University and Scientific and Technological Research (FIRST 2001).

  • ABBREVIATIONS: CB, cannabinoid; CBD, cannabidiol; THC, Δ9-tetrahydrocannabinol; VR, vanilloid receptor; AEA, N-arachidonoylethanolamide (anandamide); MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide; PMA, phorbol 12-myristate 13-acetate; WIN 55,212-2,R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate; SR141716A (SR2), N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboximide hydrochloride; SR144528 (SR1), N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; PBS, phosphate-buffered saline; PI, propidium iodide; ssDNA, single-strand DNA; ELISA, enzyme-linked immunosorbent assay; CPZ, capsazepine; PTX, pertussis toxin.

  • DOI: 10.1124/jpet.103.061002.

    • Received October 3, 2003.
    • Accepted November 7, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleCELLULAR AND MOLECULAR

Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Paola Massi, Angelo Vaccani, Stefania Ceruti, Arianna Colombo, Maria P. Abbracchio and Daniela Parolaro
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 838-845; DOI: https://doi.org/10.1124/jpet.103.061002

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Research ArticleCELLULAR AND MOLECULAR

Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Paola Massi, Angelo Vaccani, Stefania Ceruti, Arianna Colombo, Maria P. Abbracchio and Daniela Parolaro
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 838-845; DOI: https://doi.org/10.1124/jpet.103.061002
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