Abstract
Glioblastoma is a malignant brain tumor and one of the most lethal cancers in human. Temozolomide constitutes the standard chemotherapeutic agent, but only shows limited efficacy in glioblastoma patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter status. Recently, it has been shown that glioblastoma cells communicate via particular ion-channels—so-called gap junctions. Interestingly, inhibition of these ion channels has been reported to render MGMT promoter-methylated glioblastoma cells more susceptible for a therapy with temozolomide. However, given the percentage of about 65% of glioblastoma patients with an unmethylated MGMT promoter methylation status, this treatment strategy is limited to only a minority of glioblastoma patients. In the present study we show that—in contrast to temozolomide—pharmacological inhibition of intercellular cytosolic traffic via gap junctions reinforces the antitumoral effects of chemotherapeutic agent lomustine, independent of MGMT promoter methylation status. In view of the growing interest of lomustine in glioblastoma first and second line therapy, these findings might provide a clinically-feasible way to profoundly augment chemotherapeutic effects for all glioblastoma patients.
Highlights
IntroductionGlioblastoma cells have been shown to assemble to a multicellular communicating network based on ultra-long and interconnecting membrane protrusions—so-called tumor creativecommons.org/licenses/by/ 4.0/)
methylguanine-DNA methyltransferase (MGMT) promoter methylation analysis revealed a significant hypermethylation of the MGMT promoter in the investigated region of the MGMT gene for G6 and G8 cell populations, whereas G32 exhibited an unmethylated MGMT promoter status as determined by pyrosequencing (Figure 1)
We asked whether drug repurposing of MFA in the context of glioblastoma might sufficiently block intercellular gap junctionmediated calcein dye transfer as a surrogate readout for intercellular cytosolic traffic within preformed TM-based glioblastoma networks
Summary
Glioblastoma cells have been shown to assemble to a multicellular communicating network based on ultra-long and interconnecting membrane protrusions—so-called tumor creativecommons.org/licenses/by/ 4.0/). Pharmaceuticals 2021, 14, 195 microtubes (TMs) [1,2]. (Cx43)-based gap junctions that mediate intercellular cytosolic exchange and tumor tissue homeostasis [2]. We have demonstrated that pharmacological inhibition of gap junctions via INI-0602, a novel experimental gap junction inhibitor, increased the susceptibility of O6methylguanine-DNA methyltransferase (MGMT) promoter methylated glioblastoma cells to standard chemotherapeutic agent temozolomide (TMZ) [4]. Together with other in vitro studies that suggested gap junction inhibition to render glioblastoma cells more vulnerable to TMZ therapy [5,6,7], these findings raise hope for novel therapeutic implementations
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