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The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth

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Abstract

Glioblastomas (GBMs), the most common and lethal primary brain tumor, show inherent infiltrative nature and high molecular heterogeneity that make complete surgical resection unfeasible and unresponsive to conventional adjuvant therapy. Due to their fast growth rate even under hypoxic and acidic conditions, GBM cells can conserve the intracellular pH at physiological range by overexpressing membrane-bound carbonic anhydrases (CAs). The synthetic sulfonamide E7070 is a potent inhibitor of CAs that harbors putative anticancer properties; however, this drug has still not been tested in GBMs. The present study aimed to evaluate the effects of E7070 on CA9 and CA12 enzymes in GBM cells as well as in the tumor cell growth, migration, invasion, and resistance to radiotherapy and chemotherapy. We found that E7070 treatment significantly reduced tumor cell growth and increased radio- and chemotherapy efficacy against GBM cells under hypoxia. Our data suggests that E7070 has therapeutic potential as a radio-chemo-sensitizing in drug-resistant GBMs, representing an attractive strategy to improve the adjuvant therapy. We showed that CA9 and CA12 represent potentially valuable therapeutic targets that should be further investigated as useful diagnostic and prognostic biomarkers for GBM tailored therapy.

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Data Availability

The datasets supporting the conclusions of this article are included within the article and additional files.

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Acknowledgements

We thank Prof. Dr. Aguinaldo Luiz Simões for providing the authentication of the cell lines. We thank Prof. Dr. Eduardo Magalhães Rego, Cleide Lúcia Araújo Silva, and Prajna Behera for providing animal assistance.

Funding

This research was supported by grants from The São Paulo Research Foundation (FAPESP), process numbers 2011/05957–6, 2011/07448–1, and 2014/08899–5.

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Authors and Affiliations

  1. Department of Paediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Silvia A. Teixeira, Veridiana K. Suazo, Luiz Gonzaga Tone & Carlos A. Scrideli

  2. Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Silvia A. Teixeira, Mariano S. Viapiano & Mohan S. Nandhu

  3. Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Rua Antenor Duarte Villela, 1331, Barretos, SP, 14784-400, Brazil

    Silvia A. Teixeira, Lucas T. Bidinotto & Luciano Neder

  4. Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    Mariano S. Viapiano & Mohan S. Nandhu

  5. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Augusto F. Andrade

  6. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Julia A. Pezuk & Luiz Gonzaga Tone

  7. Department of Pathology, School of Medicine, UNESP – Univ. Estadual Paulista, Botucatu, São Paulo, Brazil

    Lucas T. Bidinotto

  8. Barretos School of Health Sciences, Dr. Paulo Prata – FACISB, Barretos, São Paulo, Brazil

    Lucas T. Bidinotto

  9. Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Luciano Neder

  10. Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Carlos G. Carlotti

  11. Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA

    Aline P. Becker

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  1. Silvia A. Teixeira
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  2. Mariano S. Viapiano
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Contributions

All the authors contributed to the study conception and design. Silvia A. Teixeira, Augusto F. Andrade, Julia A. Pezuk, and Veridiana K. Suazo designed, performed, and analyzed in vitro experiments. Silvia Teixeira, Augusto F. Andrade, Julia A. Pezuk, Mariano S. Viapiano, and Mohan S. Nandhu designed, and provided assistance with animal surgery and reagent preparation. Mariano S. Viapiano and Mohan S. Nandhu provided assistance to cell migration and radiotherapy experiments and orthotopic models. Aline P. Becker and Luciano Neder analyzed H&E slides. Lucas T. Bidinotto performed in silico analysis. The manuscript was written or reviewed by Silvia A. Teixeira, Augusto F. de Andrade, Mariano Sebastian Viapiano, Carlos G. Carlotti, Luiz G. Tone, and Carlos Alberto Scrideli. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Silvia A. Teixeira.

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Ethical Approval

All procedures involving animals were performed in accordance Institutional Commission of Ethics in Animal Research (CETEA) at the Ribeirão Preto Medical School, University of São Paulo (São Paulo, SP, Brazil) and Institutional Animal Care and Use Committees at Harvard Medical School/Brigham and Women's Hospital (HMA-IACUC—Boston, MA, USA). The study was carried out in compliance with the ARRIVE guidelines.

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Teixeira, S.A., Viapiano, M.S., Andrade, A.F. et al. The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth . Mol Neurobiol 58, 4520–4534 (2021). https://doi.org/10.1007/s12035-021-02437-3

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