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Natural products such as solamargine (SM), a steroidal glycoalkaloid with cytotoxic and antitumor properties, have emerged as potential adjuvant strategies. Here, we investigated the effects of SM on proliferation, clonogenic survival, morphology and migration of IDH-wildtype GB cell lines (U-87MG, U-251MG and T98-G) and non-tumoral astrocytes under normoxic and hypoxic conditions, as well as its interaction with temozolomide (TMZ). Under normoxia, SM reduced cell viability in a dose- and time-dependent manner, with IC\u2085\u2080 values between 5.04 and 9.53\u00a0\u03bcM and showed enhanced cytotoxicity under hypoxia. TMZ alone displayed modest activity, and its combination with SM produced predominantly antagonistic effects. Clonogenic assays confirmed the antiproliferative potential of SM, with significant inhibition of colony formation at 2.5\u00a0\u03bcM. SM induced marked morphological alterations but did not significantly impair migration in wound-healing assays. In U-87MG cells, SM triggered G\u2082\/M cell-cycle arrest, increased intracellular reactive oxygen species generation, and elevated \u03b3H2AX protein expression, indicating oxidative stress-associated DNA damage. However, cleaved caspase-3 and p53 were not detected, suggesting a predominantly non-apoptotic mode of cell death. Together, these findings support SM as a promising candidate for IDH-wildtype GB therapy and underscore the need for further studies to clarify its mechanisms of action and optimize its therapeutic use.<\/jats:p>","DOI":"10.1007\/s10637-026-01599-y","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:26:53Z","timestamp":1770290813000},"page":"39-47","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective cytotoxicity of solamargine via oxidative stress and caspase-independent mechanisms in human glioblastoma cells"],"prefix":"10.1007","volume":"44","author":[{"given":"Arthur Barcelos","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"de Melo Junqueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo Andrade","family":"Furtado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jairo Kenupp","family":"Bastos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise Crispim","family":"Tavares","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"1599_CR1","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","volume":"23","author":"DN Louis","year":"2021","unstructured":"Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. 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