期刊论文详细信息
Journal of Experimental & Clinical Cancer Research
Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives
Stefania Girotto1  Beatrice Balboni2  Luca M. G. Palloni3  Michele Mazzanti3  Francesca Cianci3  Ivan Verduci3  Gaetano Cannavale3  Michele Tonelli4  Silvia Schenone4  Valeria Francesconi4  Samanta Mazzetti5  Antonio Daga6  Paolo Malatesta6  Pietro Fiaschi7  Gianluigi Zona7  Federica Barbieri8  Adriana Bajetto8  Alessia Graziana Bosio8  Stefano Thellung8  Alessandra Pattarozzi8  Tullio Florio9 
[1] Computational and Chemical Biology, Fondazione Istituto Italiano di Tecnologia, 16163, Genoa, Italy;Computational and Chemical Biology, Fondazione Istituto Italiano di Tecnologia, 16163, Genoa, Italy;Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy;Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20133, Milan, Italy;Dipartimento di Farmacia, Università di Genova, 16132, Genoa, Italy;Fondazione Grigioni per il Morbo di Parkinson, 20135, Milan, Italy;IRCCS, Ospedale Policlinico San Martino, 16132, Genoa, Italy;IRCCS, Ospedale Policlinico San Martino, 16132, Genoa, Italy;Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova, 16132, Genoa, Italy;Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Viale Benedetto Xv, 2, 16132, Genoa, Italy;Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Viale Benedetto Xv, 2, 16132, Genoa, Italy;IRCCS, Ospedale Policlinico San Martino, 16132, Genoa, Italy;
关键词: Glioblastoma stem cells;    Targeted therapy;    CLIC1;    Biguanide derivatives;    GBM organoids;   
DOI  :  10.1186/s13046-021-02213-0
来源: Springer
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【 摘 要 】

BackgroundChloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings.MethodsWe synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos).ResultsWe identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity.ConclusionsThese data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.

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