# Centratherin Exhibits Antitumor Activity Against Glioblastoma Cells

## TL;DR

Centratherin, a natural compound, shows promise in fighting glioblastoma by killing cancer cells and reducing their harmful traits.

## Contribution

The study demonstrates centratherin's selective antitumor activity against glioblastoma cells without harming healthy brain cells.

## Key findings

- Centratherin reduced glioblastoma cell viability and disrupted cytoskeletal organization.
- It induced DNA damage and cell death primarily via necrosis, not necroptosis.
- Centratherin did not enhance the effect of temozolomide but killed cancer stem-like cells.

## Abstract

Glioblastoma (GB) is the most aggressive and lethal primary brain tumor, characterized by high proliferative, migratory, and invasive capacities, as well as marked resistance to apoptosis. Despite standard therapy with temozolomide (TMZ), prognosis remains poor, underscoring the need for novel therapeutic strategies. In this study, we investigated the antitumor potential of centratherin, a sesquiterpene lactone, in established GB cell lines and patient-derived GB cells (GBM02, GBM95). Centratherin significantly reduced cell viability in a dose-dependent manner, with IC50 values varying across GB cells, while exhibiting no cytotoxicity to healthy human astrocytes. Functional assays revealed that centratherin impairs cell proliferation, migration, and invasion, and alters cytoskeletal architecture, as evidenced by morphological changes, reduced actin and tubulin organization. Additionally, centratherin induced double-strand DNA breaks, increased γH2AX levels, and triggered cell death predominantly via necrosis, as demonstrated by LIVE/DEAD staining, Annexin V/PI flow cytometry, and ultrastructural analysis. Notably, this cytotoxic effect did not involve necroptosis, as RIP1 expression and Nec-1 sensitivity were unchanged. Furthermore, centratherin failed to sensitize GB cells to TMZ, suggesting distinct mechanisms of action, in spite of its remarked effect on inducing cell death in GB cancer stem-like cells. Overall, our findings highlight centratherin as a promising selective cytotoxic agent against GB, capable of inducing cell death and disrupting key malignant phenotypes, which may be advantageous for GB treatment.

The online version contains supplementary material available at 10.1007/s11064-025-04659-6.