In vitro cytotoxic mechanisms of Pt(O,O′-acac)(γ-acac)(DMS): mitochondrial dysfunction and impaired autophagy in U251 cell line

Glioblastoma stands as the deadliest primary brain malignancy in adults, primarily due to its resistance to conventional treatments and the restrictive nature of the blood-brain barrier (BBB). Cisplatin (CDDP), a widely used chemotherapeutic, demonstrates limited efficacy against glioblastoma owing to systemic toxicity and insufficient BBB penetration. To overcome these hurdles, we tested the platinum(II) complex [Pt(O,O'-acac)(γ-acac)(DMS)], indicated as Pt(acac)₂(DMS), known for its improved lipophilicity, ability to disrupt mitochondrial function, and reduced neurotoxic profile. Compared to CDDP, Pt(acac)₂(DMS) induced a targeted and prolonged cytotoxic response in U251 glioblastoma cells, promoting mitochondrial dysfunction, cell cycle arrest, and modulation of autophagy, while sparing primary human astrocytes. Our findings indicate that Pt(acac)₂(DMS) may overcome key limitations of cisplatin, including toxicity issues and resistance associated with autophagic adaptation, highlighting its promise as a potential therapeutic candidate for glioblastoma treatment.