αCT1 Peptide Sensitizes Glioma Cells to Temozolomide in a Glioblastoma Organoid Platform
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Date
2022-05
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The Ohio State University
Abstract
Glioblastoma (GBM) is the most aggressive type of brain tumor. Despite aggressive treatment, recurrence is universal. Temozolomide (TMZ) is the most common therapeutic compound employed in GBM chemotherapy since it is one of the very few drugs that can cross the blood-brain barrier (BBB). However, in the clinic, TMZ has shown limited efficacy due to the ability to evade chemotherapy in some GBM cell subpopulations, such as glioma stem cells (GSCs). Emerging evidence implicates that connexin 43 (Cx43) hemichannels are essential for mediating mass transportation in most GBM cells as the drug efflux machinery. Cx43 enables GBM chemotherapy-resistance by pumping TMZ out of the cells. Thus, inhibition of Cx43 hemichannels could mitigate drug efflux and sensitize GSCs and GBMs to TMZ. Here we evaluate the potential of two Cx43-mimetic peptides,αCT11 and αCT1, to inhibit Cx43 hemichannels and sensitize GSC-like cells and other GBM cell populations to TMZ in a 3D hyaluronic acid (HA) and collagen hydrogel-based tumor organoid model. The results of the current study demonstrated that αCT11 had no statically significant effect on the viability of TMZ treated
organoids. However, the combinatorial treatment with TMZ and αCT1 significantly enhanced TMZ efficacy in the tested cell lines compared to the TMZ-only treatment. Particularly, the GSC-like cells that are often responsible for clinical chemotherapy-resistance, showed a drastic decrease in viability after the combinatorial treatment. Immunofluorescence microscopy indicated that Cx43 is expressed in all tested cell lines, and the combinatorial treatment increased the number of Cx43 aggregates in the cell lines that responded to the treatment.
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Keywords
Glioblastoma, Organoid, Connexin 43, Cancer Engineering