{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:46:11Z","timestamp":1792802771519,"version":"4.5.0"},"reference-count":232,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glioblastoma (GBM) is one of the most invasive central nervous system tumors, with rising global incidence. Therapy resistance and poor prognosis highlight the urgent need for new anticancer drugs. Plant alkaloids, a largely unexplored yet promising class of compounds, have previously contributed to oncology treatments. While past reviews provided selective insights, this review aims to collectively compare data from the last decade on (1) plant alkaloid-based anticancer drugs, (2) alkaloid transport across the blood\u2013brain barrier (BBB) in vitro and in vivo, (3) alkaloid mechanisms of action in glioblastoma models (in vitro, in vivo, ex vivo, and in silico), and (4) cytotoxicity and safety profiles. Additionally, innovative drug delivery systems (e.g., nanoparticles and liposomes) are discussed. Focusing on preclinical studies of single plant alkaloids, this review includes 22 botanical families and 28 alkaloids that demonstrated anti-GBM activity. Most alkaloids act in a concentration-dependent manner by (1) reducing glioma cell viability, (2) suppressing proliferation, (3) inhibiting migration and invasion, (4) inducing cell death, (5) downregulating Bcl-2 and key signaling pathways, (6) exhibiting antiangiogenic effects, (7) reducing tumor weight, and (8) improving survival rates. The toxic and adverse effect analysis suggests that alkaloids such as noscapine, lycorine, capsaicin, chelerythrine, caffeine, boldine, and colchicine show favorable therapeutic potential. However, tetrandrine, nitidine, harmine, harmaline, cyclopamine, cocaine, and brucine may pose greater risks than benefits. Piperine\u2019s toxicity and berberine\u2019s poor bioavailability suggest the need for novel drug formulations. Several alkaloids (kukoamine A, cyclovirobuxine D, \u03b1-solanine, oxymatrine, rutaecarpine, and evodiamine) require further pharmacological and toxicological evaluation. Overall, while plant alkaloids show promise in glioblastoma therapy, progress in assessing their BBB penetration remains limited. More comprehensive studies integrating glioma research and advanced drug delivery technologies are needed.<\/jats:p>","DOI":"10.3390\/molecules30071561","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T05:29:19Z","timestamp":1743485359000},"page":"1561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Plant Alkaloids as Promising Anticancer Compounds with Blood\u2013Brain Barrier Penetration in the Treatment of Glioblastoma: In Vitro and In Vivo Models"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2305-3116","authenticated-orcid":false,"given":"Marcin","family":"O\u017carowski","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants\u2014National Research Institute, Wojska Polskiego 71b, 60-630 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6599-9204","authenticated-orcid":false,"given":"Tomasz M.","family":"Karpi\u0144ski","sequence":"additional","affiliation":[{"name":"Chair and Department of Medical Microbiology, Pozna\u0144 University of Medical Sciences, Rokietnicka 10, 60-806 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogus\u0142aw","family":"Czerny","sequence":"additional","affiliation":[{"name":"Department of General Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, \u017bo\u0142nierska 48, 70-204 Szczecin, Poland"},{"name":"Institute of Natural Fibres and Medicinal Plants\u2014National Research Institute, Wojska Polskiego 71b, 60-630 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Kami\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Independent Public Clinical Hospital No. 1, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Seremak-Mrozikiewicz","sequence":"additional","affiliation":[{"name":"Division of Perinatology and Women\u2019s Disease, Pozna\u0144 University of Medical Sciences, Polna 33, 60-535 Pozna\u0144, Poland"},{"name":"Laboratory of Molecular Biology in Division of Perinatology and Women\u2019s Diseases, University of Medical Sciences, Polna 33, 60-535 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The Epidemiology of Glioma in Adults: A \u201cState of the Science\u201d Review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S1474-4422(18)30468-X","article-title":"Global, Regional, and National Burden of Brain and Other CNS Cancer, 1990\u20132016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Patel","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_3","first-page":"e8195","article-title":"Rising Incidence of Glioblastoma Multiforme in a Well-Defined Population","volume":"12","author":"Grech","year":"2020","journal-title":"Cureus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.3892\/ijo.2015.2944","article-title":"Epithelial-to-Mesenchymal Transition in Paired Human Primary and Recurrent Glioblastomas","volume":"46","author":"Kubelt","year":"2015","journal-title":"Int. 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