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Assessment of Rocaglates and Targeted Derivatives as Selective Inhibitors of Glioblastoma Stem Cells

ABSTRACT: A substantial body of evidence suggests that the initiation, progression, and recurrence of glioblastomas (GBM) are driven by a small subpopulation (1-5%) of cells within the tumor known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance mechanisms and tumor relapse. As a prospective avenue for GBM intervention, targeted suppression of GBM CSCs holds promise. In this study, we identified novel rocaglate derivatives (rocaglate acyl sulfamides (Roc ASFs)) that can inhibit GBM CSCs with nanomolar (nM) EC50s. Our findings, supported by comparative dose-response assays and functional characterizations, demonstrate that these derivatives exert a robust, dose-dependent cytotoxic impact on GBM CSCs. Furthermore, our investigations into target identification have unveiled the DEAD box helicase DDX3X as a specific target of Roc ASFs. Inhibiting DDX3X using Roc ASF derivatives confers selective cytotoxicity to GBM CSCs. These findings suggest a promising therapeutic strategy for targeting GBM CSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246936 | GEO | 2024/09/13

REPOSITORIES: GEO

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Project description:Glioblastoma multiforme (GBM), is the most common form of adult malignant brain tumor, highly heterogeneous and relatively resistant to therapy with a poor prognosis. As other cancers, GBM starts from a relatively small fraction of poorly differentiated and particularly aggressive cancer stem cells (CSCs), responsible for aberrant proliferation and invasion, rapidly spreading the tumor growth in the other parts of the central nervous system. Due to the extreme tumor heterogeneity, standard therapies (i.e., surgery, chemotherapy and radiotherapy) provide poor positive outcomes and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary for searching effective therapeutic strategies against GBM. Among many emerging new therapeutic strategies, ultra-short pulsed electric fields (PEF) are considered extremely promising in cancer therapy and our previous results demonstrated the capability of a specific electric pulse protocol, characterized by a high pulse amplitude and a short duration, to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells, and of U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independently of CSCs content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the clonogenic potential, reducing the ability to form new neurospheres, and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stemness/differentiation genes. Our results, confirm this physical stimulus as a promising treatment to destabilize the extreme intra-tumoral GBM heterogeneity opening up the possibility to develop future therapeutic strategies mediated by PEF exposure.

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Assessment of Rocaglates and Targeted Derivatives as Selective Inhibitors of Glioblastoma Stem Cells

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