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Biochem Pharmacol. 2018 Nov;157:275-284. doi: 10.1016/j.bcp.2018.08.023. Epub 2018 Aug 18.

Optimization of a preclinical therapy of cannabinoids in combination with temozolomide against glioma.

Author information

1
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain; Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain.
2
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
3
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Spain.
4
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
5
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Spain.
6
Neuro-oncology Unit, Hospital Universitario, 12 de Octubre, Madrid, Spain.
7
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain; Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain. Electronic address: gvelasco@ucm.es.

Abstract

Glioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease. Δ9-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these anticancer actions relies, at least in part, on the ability of these compounds to stimulate autophagy-mediated apoptosis in tumor cells. Previous observations from our group demonstrated that local administration of THC (or of THC + CBD at a 1:1 ratio, a mixture that resembles the composition of the cannabinoid-based medicine Sativex®) in combination with Temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. With the aim of optimizing the possible clinical utilization of cannabinoids in anti-GBM therapies, in this work we explored the anticancer efficacy of the systemic administration of cannabinoids in combination with TMZ in preclinical models of glioma. Our results show that oral administration of Sativex-like extracts (containing THC and CBD at a 1:1 ratio) in combination with TMZ produces a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts. In contrast, combined administration of Sativex-like and BCNU (another alkylating agent used for the treatment of GBM which share structural similarities with the TMZ) did not show a stronger effect than individual treatments. Altogether, our findings support the notion that the combined administration of TMZ and oral cannabinoids could be therapeutically exploited for the management of GBM.

KEYWORDS:

Cannabinoids; Combinational therapies; Glioma; Temozolomide; Tumor xenografts

PMID:
30125556
DOI:
10.1016/j.bcp.2018.08.023

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