Volume 47, Issue 3, September 2004, Pages 315–323
Hypothesis: cannabinoid therapy for the treatment of gliomas?
- Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Avenida Complutense, sn, 28040 Madrid, Spain
Abstract
Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer. Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative. During the last few years, several studies have shown that cannabinoids—the active components of the plant Cannabis sativa and their derivatives—slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.
Keywords
- Glioma;
- Glioblastoma multiforme;
- Cannabinoid;
- Apoptosis;
- Angiogenesis;
- Ceramide
Figures and tables from this article:
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Fig. 1.
Chemical structure of Δ9-tetrahydrocannabinol and the endocannabinoids anandamide and 2-arachidonoylglycerol.
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Fig. 2.
Speculative model of cannabinoid antitumoural action in gliomas. (A) An early stage glioma; (B) The high proliferation rate of tumour cells leads to increased growth and therefore enhanced blood supply demand of gliomas. This leads in turn to the production of proangiogenic factors such as VEGF and of enzymes that allow tissue breakdown and remodelling such as MMP2; (C) Cannabinoids may mediate their antitumoural actions in gliomas via two mechanisms: induction of apoptosis—and perhaps growth arrest—of glioma cells, and inhibition of tumour angiogenesis. The latter effect could depend on (i) a direct action of cannabinoids on tumour cells by inhibiting proangiogenic factor production, and (ii) the inhibition of vascular endothelial cell migration and survival. In addition, cannabinoids might inhibit the expression of matrix metalloproteinases and other factors potentially involved in tumour cell invasiveness.
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Fig. 3.
Intracellular mechanisms of cannabinoid antitumoural action in gliomas. Inactivation of PTEN and overexpression of EGFR—or a constitutively active form of this receptor—are two of the most frequent alterations found in human gliomas. Tumours carrying these modifications would normally exhibit increased Akt activity, leading in turn to resistance to apoptosis and increased cell proliferation. Cannabinoid treatment may attenuate such alterations in glioma cells by inducing serine palmitoyltransferase (SPT) and promoting ceramide accumulation and Akt inhibition, which would decrease the phosphorylation of Akt and its downstream targets. In addition, ceramide induces the sustained stimulation of the Raf-1/MEK/ERK pathway, which has been shown to be involved in cannabinoid-induced apoptosis. Ceramide may also attenuate the production of the proangiogenic factor VEGF. Red lines: pathways affected by cannabinoids in glioma cells; dotted lines: other potential targets of cannabinoid antitumoural action in glioma cells; (+) activation; (−) inhibition.
- Corresponding author. Tel.: +34-913944668; fax: +34-913944672.
Copyright © 2004 Elsevier Ltd. All rights reserved.
