{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:52:04Z","timestamp":1792173124719,"version":"4.4.0"},"reference-count":90,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke (NINDS\/NIH)","award":["1R61NS128232"],"award-info":[{"award-number":["1R61NS128232"]}]},{"name":"University of Cincinnati Brain Tumor Center","award":["1R61NS128232"],"award-info":[{"award-number":["1R61NS128232"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.<\/jats:p>","DOI":"10.3390\/ijms25063217","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T12:14:40Z","timestamp":1710245680000},"page":"3217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1617-4828","authenticated-orcid":false,"given":"Aniruddha S.","family":"Karve","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8673-1327","authenticated-orcid":false,"given":"Janki M.","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth N.","family":"Gadgil","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimita","family":"Dave","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"},{"name":"Lapix Therapeutics, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha M.","family":"Wise-Draper","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A.","family":"Gudelsky","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy N.","family":"Phoenix","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biplab","family":"DasGupta","sequence":"additional","affiliation":[{"name":"Division of Oncology, Cincinnati Children\u2019s Hospital, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalanthica","family":"Yogendran","sequence":"additional","affiliation":[{"name":"Department of Neurology & Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4577-1397","authenticated-orcid":false,"given":"Soma","family":"Sengupta","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, USA"},{"name":"Department of Neurosurgery, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7568-1400","authenticated-orcid":false,"given":"David R.","family":"Plas","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj B.","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Grochans, S., Cybulska, A.M., Simi\u0144ska, D., Korbecki, J., Kojder, K., Chlubek, D., and Baranowska-Bosiacka, I. (2022). Epidemiology of Glioblastoma Multiforme-Literature Review. 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