Abstract
Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 μM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 μM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 μM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.
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Data and Material Availability
The datasets during the current study are available from the corresponding author on reasonable request.
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KS contributed to conceptualization, methodology, formal Analysis, investigation, resources, data curation, writing—original draft, and visualization. ST contributed to conceptualization, methodology, investigation, data curation, and visualization. SN contributed to formal analysis, data curation, and supervision. YE contributed to methodology, supervision, formal analysis, and writing—review & editing. NN contributed to supervision and writing—review & editing. MS contributed to formal analysis and supervision. TI contributed to supervision, writing—review & editing, and project administration. HH contributed to conceptualization, writing—review & editing, supervision, and project administration. All authors have read and agreed to the published version of the manuscript.
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The Animal Experiment Committee of Gifu Pharmaceutical University (Japan) (Ethic nos. 2020-093) reviewed and approved the animal procedures. Experiments were done according to the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.
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Shoda, K., Tsuji, S., Nakamura, S. et al. Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK. Cell Mol Neurobiol 43, 879–892 (2023). https://doi.org/10.1007/s10571-022-01221-8
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DOI: https://doi.org/10.1007/s10571-022-01221-8