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Nitric Oxide Synthase Inhibition Prevents Cell Proliferation in Glioblastoma

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Abstract

Glioblastoma multiforme (GBM) is a prevalent and aggressive primary brain tumor, presenting substantial treatment challenges and high relapse rates. GBM is characterized by alterations in molecular signaling and enzyme expression within malignant cells. This tumor exhibits elevated nitric oxide (NO.) levels. NO. is a crucial signaling molecule involved in the regulation of neuronal functions, synaptic transmission, and cell proliferation. It is primarily synthesized from L-arginine by nitric oxide synthase (NOS) enzymes. The increased levels of NO. in GBM stem from dysregulated activity and expression of clinically relevant NOS isoforms, particularly inducible NOS (iNOS) and neuronal NOS (nNOS). Based on this knowledge, we hypothesize that targeted pharmacological intervention with N6-(1-iminoethyl)-L-lysine (L-NIL), an iNOS inhibitor, and 7-Nitroindazole (7-NI), an nNOS inhibitor, may suggest a promising therapeutic strategy for the treatment of GBM. To test our hypothesis, we utilized the U87-MG cell line as an in vitro model of GBM. Our results showed that treatment with L-NIL and 7-NI led to a reduction in NO. levels, NOS activity, and clonogenic proliferation in U87-MG cells. These findings suggest that NO. and NOS enzymes might be prospective therapeutic targets for GBM.

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Funding

This work was funded by an Israeli Science Foundation (ISF) grant, an Eagles Autism Foundation grant, a National Institute of Psychobiology in Israel (NIPI) grant, an Israeli Council for Higher Education Maof grant, and a Berettler Centre for Research in Molecular Pharmacology and Therapeutics grant. The authors also thank the Satell Family and the Neubauer Family Foundation.

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Authors and Affiliations

  1. Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Daniel Kruglyakov, Shashank Kumar Ojha, Maryam Kartawy, Manish Kumar Tripathi, Wajeha Hamoudi, Wisam Bazbaz, Igor Khaliulin & Haitham Amal

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  1. Daniel Kruglyakov
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  2. Shashank Kumar Ojha
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  3. Maryam Kartawy
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  8. Haitham Amal
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Contributions

DK: conducted experiments, manuscript preparation SKO: conducted experiments MK conducted experiments MKT: conducted experiments, manuscript preparation WH: conducted experiments WB: conducted experiments IG: manuscript preparation HA: project supervision, manuscript preparationAll authors reviewed the manuscript.

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Correspondence to Haitham Amal.

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The research was partially funded by an American Pharma Company under the terms of a Research and License agreement.

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Kruglyakov, D., Ojha, S.K., Kartawy, M. et al. Nitric Oxide Synthase Inhibition Prevents Cell Proliferation in Glioblastoma. J Mol Neurosci 73, 875–883 (2023). https://doi.org/10.1007/s12031-023-02166-3

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