 Nitric oxide synthase inhibitors as potential therapeutic agents for gliomas: A systematic review

MARTIN A. MERENZON, ; ELSA HINCAPIE ARIAS,; SHOVAN BHATIA, ; ASHISH H. SHAHA,; DOMINIQU E M.O. HIGGINS; MARCELA VILLAVERDE, ; DENISE BELGOROSKY, ; ANA M. EIJÁN

NITRIC OXIDE-BIOLOGY AND CHEMISTRY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2023 vol. 138 p. 10 - 16

1089-8603

Introduction: Gliomas represent the most prevalent form of brain tumors, among which glioblastomas are the most malignant subtype. Despite advances in comprehending their biology and treatment strategies, median survival remains disappointingly low. Inflammatory processes involving nitric oxide (NO), critically contribute to glioma formation. The inducible isoform of NO synthase (iNOS) is highly overexpressed in gliomas and has been linked to resistance against temozolomide treatment, neoplastic transformation, and modulation of immune response. While both in vitro and in vivo studies showed the potential of iNOS inhibitors as effective treatments for gliomas, no clinical trials on gliomas have been published. This review aims to summarize the available evidence regarding iNOS as a target for glioma treatment, focusing on clinically relevant data.Methods: Following PRISMA guidelines, we conducted a systematic review by searching PubMed/Medline, Embase, and Scopus databases in December 2022. We included studies that investigated the impact of NOS inhibitors on glioma cells using L-NMMA, CM544, L-NAME, or OKN-007 either alone or combined with TMZ. We extracted data on the NOS inhibitor used, subtype, study setting, animal model or cell lines employed, obtained results, and safety profile. Our inclusion criteria encompassed original articles in English or Spanish, studies with an untreated control group, and a primary outcome focused on the biological effects on glioma cells.Results: Out of 319 articles screened from the aforementioned databases, 33 reports were assessed for eligibility. After excluding studies that did not utilize glioma cells or address the designated outcome, twelve original articles satisfied the inclusion and exclusion criteria. Although no NOS inhibitor has been tested in a published clinical trial, four inhibitors have been evaluated using in vivo models of intracranial gliomas. Among these, OKN 007 showed the most promising results and is currently being assessed in ongoing clinical trials. L-NAME, 1400W, and CM544 were tested in vitro. Co-administration of L-NAME or CM544 with TMZ showed superior results in vitro compared to individual agent testing. Conclusion: Glioblastoma remains a challenging therapeutic target. iNOS inhibitors exhibit substantial potential as treatment options for oncologic lesions, and they have demonstrated a safe toxicity profile in humans for other pathological conditions. Research endeavors should be focused on investigating their potential effects on brain tumors.