In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions. Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis. However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation. In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.

Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel^®, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics.

Introduction/Objectives: Implicated in the regionalization of the anterior central nervous system (CNS) and the progression of pallial astrogliogenesis, the transcription factor gene EMX2 has been reported to be specifically silenced in several tumors, both non-neural and neural. Based on that, its overexpression has been proposed as a tool for the treatment of a subset of these malignancies, including glioblastoma. Here we tested this proposal. Methods/Results: We found that Emx2 overexpression in human glioblastoma cells transplanted into the striatum of immunotolerant mice significantly prolonged animals’ survival, outperforming their treatment by temozolomide. However, this approach did not eradicate the tumor, because of in vivo silencing of the therapeutic Emx2 transgene. Notably, silencing of this transgene (or of a reporter designed to monitor its competence to be expressed) also occurred during long-term in vitro culture of GBM cells and was exacerbated by coculture with murine pallial glia under hypoxic conditions. Remarkably, partial insulation of the transgene and the use of a specific combination of epigenetic drugs substantially counteracted the progressive activatability decline undergone by the Emx2-transgene expression reporter, suggesting a promising strategy for overcoming a major limitation of Emx2-based therapy for GBM. Conclusions: An Emx2-encoding transgene, protected by insulation and appropriate epigenetic drugs, can provide a substantial benefit in experimental therapy for glioblastoma.