Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect

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Abstract

In the present study, we found that CBD inhibited U87-MG and T98G cell proliferation and invasiveness in vitro and caused a decrease in the expression of a set of proteins specifically involved in growth, invasion and angiogenesis. In addition, CBD treatment caused a dose-related down-regulation of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and decreased hypoxia inducible factor HIF-1α expression in U87-MG cells. Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways. As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.

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Most cited references 37

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Hypoxia-inducible factors, stem cells, and cancer.

Brian Keith, M. Celeste Simon (2007)

Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.

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Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.

W Kolch (2000)

The Ras/Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, and how they contribute to co-ordinate activation steps, subcellular redistribution, substrate phosphorylation and cross-talk with other signalling pathways.

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Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis.

Balveen Kaur, Fatima Khwaja, Eric Severson … (2005)

Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of alpha and beta subunits. The alpha subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors alpha and beta, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation.

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Author and article information

Contributors

Guillermo Velasco: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 21 October 2013

Volume: 8

Issue: 10

Electronic Location Identifier: e76918

Affiliations

[1 ]Department of Theoretical and Applied Sciences, Biomedical Research Division, Centre of Neuroscience, University of Insubria, Busto Arsizio, Varese, Italy

[2 ]Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Milan, Italy

[3 ]Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

Complutense University, Spain

Author notes

* E-mail: daniela.parolaro@ 123456uninsubria.it

Competing Interests: GW Pharmaceuticals funded part of the research. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: MS PM MV DB MG EM DP. Performed the experiments: MS VC MV DB MG. Analyzed the data: MS VC MV DB MG. Wrote the paper: MS PM MV MG EM TR DP.

Article

Publisher ID: PONE-D-13-17551

DOI: 10.1371/journal.pone.0076918

PMC ID: 3804588

PubMed ID: 24204703

SO-VID: 34ea3a8c-b09f-4486-a4cf-c95965a8dd18

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 April 2013

Date accepted : 5 September 2013

Page count

Pages: 9

Funding

This work was supported by a grant from University of Milan-F.I.R.S.T 2008. GW Pharmaceuticals funded part of the research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect

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Most cited references 37

Hypoxia-inducible factors, stem cells, and cancer.

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.

Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis.

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