Abstract
The intermediate-conductance calcium-activated potassium channel K(Ca)3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and K(Ca)3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged ...
Abstract
The intermediate-conductance calcium-activated potassium channel K(Ca)3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and K(Ca)3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560's intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-beta 1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3(+), CD8(+) or FoxP3(+) T cells was not impacted by either irradiation or K(Ca)3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.
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