Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation

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Abstract

Δ9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture. Here, we show that intratumoral administration of Δ9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice deficient in recombination activating gene 2. Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used. Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.

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Figure 1: Cannabinoid-induced regression of malignant gliomas in Wistar rats.
Figure 2: Cannabinoid-induced regression of malignant gliomas in Rag2−/− mice.
Figure 3: Different sensitivity of C6.9 and C6.4 glioma cells to THC-induced death.
Figure 4: Short-term effect of THC on sphingomyelin hydrolysis, ceramide levels and ERK activity in C6.9 and C6.4 glioma cells.
Figure 5: Long-term effect of THC on ceramide levels and ERK, Raf1 and KSR activity in C6.9 and C6.4 glioma cells.

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Acknowledgements

We thank following: J. Palacín and his collaborators for animal handling and care; A. Royo, P. Moreno, J. Ruiz-Cabello and their collaborators for MRI procedures; M.L. de Ceballos and C. Bailón for TUNEL staining; D. Rueda for cell culture; F. Valino for computer assistance; Sanofi Recherche (Montpellier, France) for SR141716, SR144528 and the antibody against the CB2 cannabinoid receptor; A. Howlett for the anti-CB1 cannabinoid receptor antibody; J.J. Fernández Ruiz and J.A. Ramos for WIN-55,212-2 and CP-55,940; and R. Mechoulam for HU-210. This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología (PM 98-0079 to M.G., and PM98-0007 to M.I.) and Comunidad Autónoma de Madrid (8.5/17/98 to M.G., 8.1/6/97 to M.I., and 8.6/21/98 to M.I.). Severo Ochoa Molecular Biology Center is the recipient of an institutional grant from Fundación Ramón Areces.

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Correspondence to Manuel Guzmán.

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Galve-Roperh, I., Sánchez, C., Cortés, M. et al. Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6, 313–319 (2000) doi:10.1038/73171

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