Sulforaphane Decreases the Burden of AKT1-Expressing Pre-Neoplastic Cells in a Zebrafish Model of Glioblastoma Initiation

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Abstract
Background: Glioblastoma is a primary aggressive brain tumor, with an average survival rate of ~14.6 months. The low therapeutic benefit of current treatments is in part due to glioblastoma-initiating cells hijacking microglia/macrophages to support tumor growth, prompting the development of multitargeted therapeutic approaches. One such therapeutic target is transcription factor Nrf2. High Nrf2 activity is associated with high-grade tumors, and high Nrf2 levels in microglia/macrophages lead to polarization toward an immunosuppressive profile, supporting glioblastoma progression and therapy resistance. Interestingly, however, sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables and a potent Nrf2 activator, has anti-carcinogenic effects in multiple animal models. Methods: We utilized the zebrafish glioblastoma initiation model of human AKT1 overexpression in neuronal progenitors to capture the intermediate progenitor-cell-like state of glioblastoma-initiating/pre-neoplastic cells and evaluated the therapeutic potential of SFN and VVD130037, an Nrf2 inhibitor currently in clinical trials. Results: Initial findings suggest that SFN, individually and in combination with VVD130037, had the potential to decrease the levels of AKT1. Surprisingly, VVD130037 tended to increase AKT1. The pAKT1 levels also increased in Nrf2-deficient human cells. Moreover, failure to activate Nrf2 in neural progenitors in response to SFN, while a preliminary observation that warrants further investigation, suggests that the decrease in AKT1 was not potentially mediated by Nrf2 activation. The combined effect of SFN and VVD130037 on AKT1 was particularly strong in irf8-/- mutant larvae, which lack a microglia/macrophage population, indicating the existence of a non-tumorigenic cell population(s) sensitive to changes in Nrf2 activity. Conclusions: AKT1 inhibition in glioblastoma-initiating cells by the phytochemical SFN, combined with Nrf2 inhibition in the surrounding cells, may impede glioma progression.
Funding Information
  • Medical Research Council (MR/W023806/1)

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