Marta Solinas of Università degli Studi dell'Insubria, Varese (UNINSUBRIA) with expertise in: Biotechnology, Cancer Research and Microbiology. Read 6. Marta Solinas is on Facebook. Join Facebook to connect with Marta Solinas and others you may know. Facebook gives people the power to share and makes. Followers, Following, 20 Posts - See Instagram photos and videos from Marta Solinas (@marta_s88).
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. A representative western blot is shown. Similarly, in both cell lines CBD also reduced constitutive Akt phosphorylation, with no effect on total Akt protein level Fig.
A,C Western blot analysis of phospho- and pan-Akt. B,D Densitometric analysis of Akt signal bands from three independent experiments is reported. Interestingly, CBD showed similar antiproliferative effects in both hypoxic conditions and under normoxic state data not shown.
UMG and T98G glioma cells were grown under normoxia and two different hypoxic conditions see Materials and methods. Results presented herein demonstrate that the non psychoactive phytocannabinoid CBD inhibits UMG and T98G cell invasion and proliferation, and shed light on the molecular mechanisms that drive its anti-tumoral action.
The high rate of tumor cell invasiveness into normal brain tissue is a defined hallmark of gliomas and represents an important aspect accounting in large part for their poor prognosis. The ability of tumoral cells to invade the normal tissue is crucial for tumor spread, growth, and metastasis. Our results demonstrate that CBD effectively inhibited glioma cell invasion, though with different potency in the two different cell lineages considered, as tested by the matrigel Boyden assay.
The ability of CBD to reduce glioma invasiveness is in accordance with the data of Marcu et al. In the invasion assay, CBD does not seem to show a classic dose-dependent response, showing a very narrow dose range. This could be related to the fact that CBD has been previously reported to act on gliomas through a cannabinoid and vanilloid receptor-independent mechanism  ,  , .
Therefore, the lack of a classic dose-dependent effect of CBD in our matrigel experiments could be partially related to its low affinity for cannabinoid and vanilloid receptors. Moreover, other CBD pharmacological effects tested in various models are not always dose-related  ,  and even some other structure-related cannabinoids, such as HU tetrahydrocannabinol quinone and HU cannabinol quinone , were able to inhibit aortic ring angiogenesis without a clear dose-response relationship .
A second highlight of the present work is the evidence that active CBD concentrations produce a widespread inhibition of several proteins involved in cell growth and invasion in both cell lines. All these proteins are differently involved in malignancy, motility, invasion and angiogenesis. MMPs are fundamental proteases up-regulated in gliomas and strictly associated with the malignancy of these tumors .
Indeed they favour tumor cell motility, invasion and angiogenesis by degrading ECM and act as chemotactic signals . In addition, we found inhibition of TIMP-1, a stromal factor with multiple functions, whose over expression correlates with aggressive clinical behavior of a spectrum of tumors, gliomas included.
Further studies are needed to clarify the involvement of TIMPs in brain tumor progression. Indeed low levels of this protein would be expected to favour cancer cell growth, but some clinical studies have indicated that SerpinE1-PAI-1 expression is strongly related with poor outcome in cancer. At present, this apparent discrepancy is not understood and some recent reports point to other multifunctional roles of the protein in angiogenesis, invasiveness and cell adhesion .
Finally, we found that CBD significantly inhibited VEGF, one of the most potent stimuli in angiogenesis able to drive the growth of new blood vessels. MCP-1 is specifically secreted by glioma cells to inhibit antitumor immune responses and facilitate tumor growth  , . Finally, CBD determined a decrease in the potential angiogenic factor Angiogenin, whose increase significantly correlates with the higher grade of glioma malignancy .
These results suggest that CBD efficacy in inhibiting tumor growth and invasion proteins shows differences between the two considered cell lines, despite a similar potency in reducing cell viability. This may reside in the different genetic background of the two lines due to the different brain tumor subtype that they were isolated from. These signaling molecules have been shown to play a crucial role in tumor cell proliferation and in cell escape from apoptosis or cycle arrest as well as in cell motility and invasion  , .
Similar results were recently obtained by Soroceanu et al. They suggest that CBD may act through modulation of Id-1, a transcription factor regulator that seems to be involved in glioma malignancy . In addition, Akt is highly activated in gliomas and represents a nodal point in cell signaling stimulated by several upstream stimuli, including growth factors  , .
Thus, in human malignancies, kinases represent an attractive target for anticancer research and numerous kinase inhibitors are currently under investigation in human clinical trials  , . Therefore, simultaneous pharmacological inhibition of both Akt and ERK by CBD might represent a valuable effect for its potential therapeutic use in gliomas.
Recently, Marcu et al. This discrepancy is only apparent, since they used a very low CBD concentration 0. Gliomas have extensive areas of severe hypoxia and necrosis, which represent a major obstacle to the success of chemotherapy.
We still do not know the precise mechanism of action of CBD. GPR55 is an orphan G-protein linked receptor that appears up-regulated in some cancer-derived cell lines and plays a pivotal role in tumor cells . However, at the moment, the possible involvement of GPR55 and its precise role in mediating CBD effects is still controversial. In conclusion, the present investigation confirms the antiproliferative and antiinvasive effects of CBD in UMG cells.
Moreover, our data add further insights into CBD antitumor action, showing its ability to influence multiple cellular targets in the two cell lines with partial overlap. Future studies are urgently needed to highlight the molecular mechanism through which CBD can influence the different intracellular pathways taken into account in the present work.
This work was supported by a grant from University of Milan-F. 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.
National Center for Biotechnology Information , U. Published online Oct Author information Article notes Copyright and License information Disclaimer.
There are no patents, products in development or marketed products to declare. Received Apr 29; Accepted Sep 5. 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 properly credited.
This article has been cited by other articles in PMC. Abstract In the present study, we found that CBD inhibited UMG 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. Introduction Malignant gliomas are among the most rapidly growing and devastating neoplasms with poor prognosis.
Materials and Methods Reagents Standard chemicals and cell culture reagents were purchased from Sigma Aldrich. Western Blot Analysis Cells were scraped and collected by centrifugation. Open in a separate window. CBD Modifies the Expression Pattern of Tumor-related Proteins in Glioma Cells Since tumor cell growth, invasion and angiogenesis depend on complex pathways and activity of different proteins, we analyzed whether CBD interfers with the expression profile of a set of proteins involved in tumor development in glioma cells, using a rapid and sensitive antibody array-based assay.
Discussion Results presented herein demonstrate that the non psychoactive phytocannabinoid CBD inhibits UMG and T98G cell invasion and proliferation, and shed light on the molecular mechanisms that drive its anti-tumoral action.
Request Full-text from Authors. References Supplied by CrossRef. Treatment options for recurrent glioblastoma: Expert Rev Anticancer Ther Molecular mechanisms of glioma invasiveness: Nat Rev Cancer Hypoxia-inducible factors, stem cells, and cancer B Keith et al.
Genetic and hypoxic regulation of angiogenesis in gliomas B Kaur et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis B Kaur et al.
Cannabinoids for cancer treatment: Cannabidiol as potential anticancer drug P Massi et al. Br J Clin Pharmacol Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines P Massi et al.
J Pharmacol Exp Ther The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells P Massi et al. Cell Mol Life Sci Current progress in the biology of members of the Sporothrix schenckii complex following the genomic era.
Diabetes knowledge and utilization of healthcare services among patients with type 2 diabetes mellitus in Dhaka, Bangladesh. Relaxin-induced changes in renal function and RXFP1 receptor expression in the female rat. Request Full Text Paper. Please type a message to the paper's authors to explain your need for the paper. Only shared with authors of paper.
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