Glioblastoma multiforme (GBM) is among the most lethal primary brain tumors and is characterized by significant cellular heterogeneity and resistance to conventional therapies. This study investigates the efficacy of seco-duocarmycin SA (seco-DSA), a novel DNA alkylating agent. Initial investigations using a colony formation assay revealed that seco-DSA exhibits remarkable potential with IC50 values lower than its natural DSA counterpart. Cell viability assay indicated that LN18 cells showed a markedly greater sensitivity to DSA than T98G cells. Furthermore, seco-DSA achieved its full cytotoxic effect within 8 h of drug incubation in GBM cell lines. Although seco-DSA induced a concentration-dependent increase in apoptotic cell death, the extent of apoptosis did not fully account for the observed decrease in cell viability. Instead, seco-DSA treatment resulted in significant cell cycle arrest in S and G2/M phases. These findings suggest that seco-DSA's cytotoxicity in GBM cells is primarily due to its ability to disrupt cell cycle progression, though the precise mechanisms of action remain to be fully established, and further research is needed. Proteomic analysis of treated cells also indicates dysregulation of proteins involved in senescence, apoptosis, and DNA repair, alluding to seco-DSA-induced arrest as a major mechanism of GBM disruption. Data are available via ProteomeXchange with the dataset identifier "PXD061023". Our reports promote the future exploration of seco-DSA's therapeutic potential, representing a critical step toward developing a more targeted and effective treatment for GBM. [ABSTRACT FROM AUTHOR]

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