Blocking distinct interactions between Glioblastoma cells and their tissue microenvironment: A novel multi-targeted therapeutic approach

Abstract

Due to the highly invasive nature of Glioblastoma (GB), complete surgical resection is not feasible, while motile tumour cells are often associated with several specific brain structures that enhance treatment-resistance. Here, we investigate the therapeutic potential of Disulfiram and Carbenoxolone, that inhibit two distinct interactions between GB and the brain tissue microenvironment: stress-induced cell-matrix adhesion and gap junction mediated cell-cell communication, respectively. Increase in cell numbers of tumour-initiating cells, which are cultured in suspension as cell clusters, and adherent differentiated cells can be blocked to a similar extent by Carbenoxolone, as both cell populations form gap junctions, but the adherent differentiated cells are much more sensitive to Disulfiram treatment, which – via modulation of NF-κB signalling – interferes with cell-substrate adhesion. Interestingly, inducing adhesion in tumour-initiating cells without differentiating them does not sensitize for Disulfiram. Importantly, combining Disulfiram, Carbenoxolone and the standard chemotherapeutic drug Temozolomide reduces tumour size in an orthotopic mouse model. Isolating GB cells from their direct environment within the brain represents an important addition to current therapeutic approaches. The blockage of cellular interactions via the clinically relevant substances Disulfiram and Carbenoxolone, has distinct effects on different cell populations within a tumour, potentially reducing motility and/or resistance to apoptosis.

Inflammation and Metabolism in Cancer Cell—Mitochondria Key Player

“…ROS-dependent therapies that target mitochondria, range from photodynamic therapy, to compounds such as retinoic acid and arsenic trioxide that directly target sub-structures (142). It has been recently shown that ROS can modulate microtubule dynamics in the course of the EB1 phosphorylation process (143).…”

Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma

“…(iv) CSPG-induced cell-ECM bonding was mediated by its receptor LAR and LAR-CSGAG complex [ 42 ]. Integrins usually mediate the cell-matrix interactions by tethering the cell to its surrounding ECM and activating intracellular signalling cascades [ 43 , 44 ].…”

“…A glioma interacts with its microenvironment such as stromal cells (astrocytes, neurons, microglia, macrophages), ECM, vessels, and chemokines/cytokines by direct and indirect contacts in the tumor-stroma network [ 42 , 43 , 47 , 48 ]. M1 and M2 types of microglia were shown to promote glioma cell invasion by exchanging signaling molecules such as CSF-1, EGF and TGF- β [ 49 – 52 ].…”

Inhibition of Gap Junctions Sensitizes Primary Glioblastoma Cells for Temozolomide

“…Current available studies on pharmacological gap junction inhibition in glioblastoma are mainly based on the use of the glycyrrhetinic acid-derivative carbenoxolone as a potent gap junction blocker [22,23,24,25,26,27]. However, carbenoxolone has been shown not to reach therapeutically relevant concentrations for gap junction inhibition in the brain interstitium after systemic administration [28].…”