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Cited by 160Cannabis and Cannabinoid ResearchGlioma Diagnosis and TreatmentCancer, Stress, Anesthesia, and Immune Response

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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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Solinas, Marta, Massi, Paola, Cinquina, Valentina, Valenti, Marta, Bolognini, Daniele, Gariboldi, Marzia, Monti, Elena, Rubino, Tiziana, Parolaro, Daniela·2013·PLoS ONE
DOI 10.1371/journal.pone.0076918PMC PMC3804588
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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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Figure 1 Effect of increasing CBD concentrations on U87-MG (A) and T98G (C) glioma cell invasion. U87-MG and T98G cells were treated with CBD, seeded onto a filter coated with matrigel and incubated for 24 h at 37°C. Cells that invaded the lower surface of the filter were quantified. The invasion was expressed as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01 vs Control [C], Dunnett’s t test. Effect of increasing CBD concentrations on U87-MG (B) and T98G (D) glioma cell viability. U87-MG and T98G glioma cells were cultured in serum-free medium with increasing concentrations of CBD. Cell viability was determined by MTT assay after 24 h of treatment. The viability was expressed as percentage of the untreated control. Data represent the mean ± S.E.M. of at least three independent experiments.
Figure 1 Effect of increasing CBD concentrations on U87-MG (A) and T98G (C) glioma cell invasion. U87-MG and T98G cells were treated with CBD, seeded onto a filter coated with matrigel and incubated for 24 h at 37°C. Cells that invaded the lower surface of the filter were quantified. The invasion was expressed as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01 vs Control [C], Dunnett’s t test. Effect of increasing CBD concentrations on U87-MG (B) and T98G (D) glioma cell viability. U87-MG and T98G glioma cells were cultured in serum-free medium with increasing concentrations of CBD. Cell viability was determined by MTT assay after 24 h of treatment. The viability was expressed as percentage of the untreated control. Data represent the mean ± S.E.M. of at least three independent experiments.CC BY · PubMed Central
Figure 2 Effect of increasing CBD concentrations on the protein expression profile of U87-MG glioma cells. U87-MG cells were treated with CBD for 24 h and supernatants were used to determine different protein levels through a human array kit/proteome profiler. (A) Representative proteomic membrane analysis with indication of the modified proteins. (B) Densitometric analysis of the membrane spots reported as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01, ***p<0.001 vs Control, Dunnett’s t test. U87-MG cells were treated with CBD for 24 h and lysates from cells were used to assess MMP-9 and TIMP-4 protein levels. (C) Western blot analysis of MMP-9 and TIMP-4. A representative western blot is shown. (D) Densitometric analysis of MMP-9 and TIMP-4 signal bands from three independent experiments is reported. **p<0.01 vs Control [C], Dunnett’s t test.
Figure 2 Effect of increasing CBD concentrations on the protein expression profile of U87-MG glioma cells. U87-MG cells were treated with CBD for 24 h and supernatants were used to determine different protein levels through a human array kit/proteome profiler. (A) Representative proteomic membrane analysis with indication of the modified proteins. (B) Densitometric analysis of the membrane spots reported as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01, ***p<0.001 vs Control, Dunnett’s t test. U87-MG cells were treated with CBD for 24 h and lysates from cells were used to assess MMP-9 and TIMP-4 protein levels. (C) Western blot analysis of MMP-9 and TIMP-4. A representative western blot is shown. (D) Densitometric analysis of MMP-9 and TIMP-4 signal bands from three independent experiments is reported. **p<0.01 vs Control [C], Dunnett’s t test.CC BY · PubMed Central
Figure 3 Effect of increasing CBD concentrations on the protein expression profile of T98G glioma cells. T98G cells were treated with CBD for 24/proteome profiler. (A) Representative proteomic membrane analysis with indication of the modified proteins. (B) Densitometric analysis of the membrane spots reported as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01 vs Control, Dunnett’s t test.
Figure 3 Effect of increasing CBD concentrations on the protein expression profile of T98G glioma cells. T98G cells were treated with CBD for 24/proteome profiler. (A) Representative proteomic membrane analysis with indication of the modified proteins. (B) Densitometric analysis of the membrane spots reported as percentage of the untreated control. Data represent the mean ± S.E.M. of three independent experiments. **p<0.01 vs Control, Dunnett’s t test.CC BY · PubMed Central
Figure 4 Effect of increasing CBD concentrations on ERK phosphorylation in U87-MG and T98G glioma cells. U87-MG and T98G cells were treated with CBD for 24 h and lysates from cells were used to assess ERK protein levels. (A,C) Western blot analysis of phospho- and total-ERK. A representative western blot is shown. (B,D) Densitometric analysis of ERK signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], Dunnett’s t test.
Figure 4 Effect of increasing CBD concentrations on ERK phosphorylation in U87-MG and T98G glioma cells. U87-MG and T98G cells were treated with CBD for 24 h and lysates from cells were used to assess ERK protein levels. (A,C) Western blot analysis of phospho- and total-ERK. A representative western blot is shown. (B,D) Densitometric analysis of ERK signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], Dunnett’s t test.CC BY · PubMed Central
Figure 5 Effect of increasing CBD concentrations on Akt phosphorylation in U87-MG and T98G glioma cells. U87-MG and T98G cells were treated with CBD for 24 h and lysates from cells were used to assess Akt protein levels. (A,C) Western blot analysis of phospho- and pan-Akt. A representative western blot is shown. (B,D) Densitometric analysis of Akt signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], Dunnett’s t test.
Figure 5 Effect of increasing CBD concentrations on Akt phosphorylation in U87-MG and T98G glioma cells. U87-MG and T98G cells were treated with CBD for 24 h and lysates from cells were used to assess Akt protein levels. (A,C) Western blot analysis of phospho- and pan-Akt. A representative western blot is shown. (B,D) Densitometric analysis of Akt signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], Dunnett’s t test.CC BY · PubMed Central
Figure 6 Effect of CBD on HIF-1α level in glioma cells grown in normoxic and hypoxic conditions. U87-MG and T98G glioma cells were grown under normoxia and two different hypoxic conditions (see Materials and methods). Cells were treated with CBD for 24 h and lysates from the cells were used to assess HIF-1α protein levels. (A–C) Western blot analysis of HIF-1α and β-actin. A representative western blot is shown. (B–D) Densitometric analysis of HIF-1α signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], ° p<0.05, °° p<0.01, °°° p<0.001, °°°° p<0.0001 vs normoxia Control [C], Dunnett’s t test.
Figure 6 Effect of CBD on HIF-1α level in glioma cells grown in normoxic and hypoxic conditions. U87-MG and T98G glioma cells were grown under normoxia and two different hypoxic conditions (see Materials and methods). Cells were treated with CBD for 24 h and lysates from the cells were used to assess HIF-1α protein levels. (A–C) Western blot analysis of HIF-1α and β-actin. A representative western blot is shown. (B–D) Densitometric analysis of HIF-1α signal bands from three independent experiments is reported. *p<0.05, **p<0.01 vs Control [C], ° p<0.05, °° p<0.01, °°° p<0.001, °°°° p<0.0001 vs normoxia Control [C], Dunnett’s t test.CC BY · PubMed Central

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Metadata

Authors
Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., & Parolaro, D.
Affiliations
  • University of Insubria (IT)
  • University of Milan (IT)
  • University of Toronto (CA)
Corresponding author
Parolaro, Daniela
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-10-21
Volume
8
Issue
10
Pages
e76918
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0076918
PMC
PMC3804588
OpenAlex
W2083034715
Cited by
159
References
47
Citations by year
2026: 14 · 2025: 8 · 2024: 17 · 2023: 22 · 2022: 21 · 2021: 24 · 2020: 14 · 2019: 10 · 2018: 9 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 3
FWCI
3.43
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IrInSubria (University of Insubria) (submittedVersion)
Funders
  • Università degli Studi di Milano
  • GW Pharmaceuticals
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
Keywords
cannabidiol, glioma, U87 cells, T98G cells, cell proliferation, tumor invasion, angiogenesis, ERK signaling, Akt signaling, HIF-1α, anticancer activity, phytocannabinoids
MeSH terms
Antineoplastic Agents, Cannabidiol, Cell Movement, Cell Survival, Dose-Response Relationship, Drug, Glioma, Humans, Neoplasm Invasiveness, Blotting, Western, Signal Transduction, Proteome, Proteomics, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Proto-Oncogene Proteins c-akt, Hypoxia-Inducible Factor 1, alpha Subunit

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