{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T03:29:05Z","timestamp":1786418945706,"version":"build-2736575974"},"reference-count":46,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>The treatment of glioblastoma remains a major clinical challenge, largely due to intrinsic and acquired resistance to Temozolomide (TMZ). We aim to advance a novel therapeutic approach to overcome TMZ resistance in human glioblastoma by using the neuronal nitric oxide synthase inhibitor BA\u2010101 as both a monotherapy and an adjuvant therapy. This approach leverages the additive anti\u2010cancer activity of BA\u2010101 to enhance the efficacy of TMZ and thereby improve treatment outcomes for glioblastoma patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We used TMZ\u2010resistant human glioblastoma LN\u201018 and LN\u2010229 cells to study the therapeutic potential and additive anticancer activity of nNOS inhibitor BA\u2010101 using in\u00a0vitro cancer functional assays, including cell proliferation, cell invasion, and migration assays, and biochemical assessment of biomarkers for nitrosative stress, and apoptosis using western blot analysis, flow cytometry and AnnexinV\/PI staining. We further performed an in\u00a0vivo preclinical evaluation\u00a0using an LN\u2010229 xenograft tumor model in SCID mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Our findings demonstrate that BA\u2010101 displays significant anti\u2010cancer activity and sensitizes resistant glioblastoma cells to TMZ, reducing nitrosative stress, inhibiting clonogenic growth, invasion and migration, and promoting apoptotic cell death. It also demonstrates a significant decrease in tumor volume, suggesting that BA\u2010101 exerts additive anti\u2010tumor activity when used as an adjuvant to TMZ in SCID mice bearing LN 229 xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Collectively, our findings strongly suggest that BA\u2010101 has potential for further preclinical and translational development as an anticancer agent and a novel TMZ chemosensitizer for GBM therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72067","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T04:11:58Z","timestamp":1782792718000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Temozolomide\u2010Resistant Glioblastoma: Therapeutic Potential of Neuronal Nitric Oxide Synthase Inhibitor"],"prefix":"10.1002","volume":"15","author":[{"given":"Mallikarjuna","family":"Nimgampalle","sequence":"first","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashank Kumar","family":"Ojha","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Kartawy","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Feivelson","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8380-2054","authenticated-orcid":false,"given":"Haitham","family":"Amal","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, Faculty of Medicine The Hebrew University of Jerusalem  Jerusalem Israel"},{"name":"The Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center Boston Children's Hospital, Harvard Medical School, Harvard University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102412"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17010146"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15072116"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol31070296"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115174"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-025-02046-4"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-025-02567-3"},{"key":"e_1_2_11_9_1","first-page":"17","article-title":"Mechanisms of Temozolomide Resistance in Glioblastoma\u2014A Comprehensive Review","volume":"4","author":"Singh N.","year":"2020","journal-title":"Cancer Drug Resistance"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1437436"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2023.09.003"},{"key":"e_1_2_11_12_1","first-page":"4891","article-title":"Function of Neuronal Nitric Oxide Synthase Enzyme in Temozolomide\u2010Induced Damage of Astrocytic Tumor Cells","volume":"15","author":"Resende F.","year":"2018","journal-title":"Oncology Letters"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2018.7527"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.11.035"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101567"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202205783"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-024-02270-y"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.06.007"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01578-2"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.61373\/bm024e.0115"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-022-01890-5"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade0764"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.620677"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2022.105281"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411286"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900580"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2023.06.002"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-023-02166-3"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.61373\/bm025r.0050"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11020231"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6820"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14092211"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-19-1162"},{"key":"e_1_2_11_34_1","first-page":"1","volume-title":"Molecular Diversity","author":"Gallorini M.","year":"2025"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00159"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21061932"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22084150"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2017.1388972"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020443"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/php.12636"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216931"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines9020094"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.278"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6107"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-3213"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e39984"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188616"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72067","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.72067","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72067","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T02:51:24Z","timestamp":1786416684000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.72067"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":46,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/cam4.72067"],"URL":"https:\/\/doi.org\/10.1002\/cam4.72067","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"2025-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72067"}}