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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
Department of Pharmacology, Chemotherapy and Toxicology (P.M., A.C.), and
Department of Pharmacological Sciences, School of Pharmacy, and Center of
Excellence for Neurodegenerative Diseases, University of Milan, Milan, Italy
(S.C., M.P.A.); and Department of Structural and Functional Biology,
Pharmacology Unit and Center of Neuroscience, University of Insubria, Busto
Arsizio (Varese), Italy (A.V., D.P.). Address correspondence to: Daniela Parolaro, Dept. of Structural and
Functional Biology, Pharmacology Unit and Center of Neuroscience, University of
Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (Varese), Italy. E-mail: daniela.parolaro@uninsubria.it.
Received October 3, 2003; accepted November 7, 2003.
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. Copyright
© 2004 by the American Society for Pharmacology and Experimental Therapeutics.
Source: http://jpet.aspetjournals.org/cgi/content/abstract/308/3/838
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