MOG-G-CCM

APR-246 Combined with Epigenetic Modulators Reduces Glioblastoma Clonogenicity

Glioblastoma remains refractory to conventional surgery, radiotherapy, and temozolomide chemotherapy, necessitating novel therapeutic strategies. Rosa et al. explored the combination of APR‑246, an agent aimed at restoring mutant p53 function, with epigenetic modulators DZ Nep (EZH2 inhibitor) and panobinostat, alongside temozolomide. Using the Chou-Talalay method, APR‑246 demonstrated additive interactions with these agents, reducing clonogenicity and inducing apoptosis irrespective of p53 status.

In adherent colony formation assays, GOS‑3 cells showed a significant reduction in colony-forming ability following combined DZ‑Nep and APR‑246 treatment compared to controls (Fig. 1A). PE8 and PE9 primary tumor cells exhibited no significant changes, whereas LN405 cells were more sensitive than their temozolomide-resistant counterpart (LN405‑TMZR) to single-agent or combined treatment. Similarly, A172‑TMZR cells were more responsive than parental A172 cells, forming fewer colonies under combination therapy. Additional cell lines (U87MG, T98G, MOG‑G‑CCM) also showed marked suppression of colony formation with dual treatment (Fig. 1A).

Soft agar assays confirmed these findings, with significant decreases in colony numbers for T98G, U87MG, and LN405 treated with APR‑246 plus DZ‑Nep (Fig. 1B). No significant reductions were observed in LN405‑TMZR or PE8 cells, and LN405‑TMZR showed increased colony formation upon APR‑246 monotherapy. These results highlight the potential of combining APR‑246 with epigenetic inhibitors to suppress glioblastoma growth, particularly in select resistant contexts.