Tropolone Derivative JO-122(2) Enhances Temozolomide Efficacy and p53-Mediated Apoptosis in Glioblastoma Xenografts.

BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with limited therapeutic options and poor survival. Resistance to standard temozolomide (TMZ) therapy remains a major challenge, necessitating novel agents. Tropolone derivatives, particularly the synthetic trichlorotropolone JO-122(2), have shown broad preclinical antitumor activity. This study aimed to determine whether JO-122(2), alone or combined with TMZ, can suppress GBM growth in vivo and to define the accompanying changes in the p53/MDM2/Bcl-2 apoptotic axis. METHODS: JO-122(2), as monotherapy or combined with TMZ, was evaluated in a U87 MG GBM xenograft model in BALB/c nude mice (n = 8 per group). Tumor volumes were monitored over 25 days, and tumor growth inhibition (TGI) was calculated. Molecular mechanisms were investigated by RT-qPCR and ELISA, assessing gene expression and protein levels of the apoptotic regulators TP53, MDM2, BAX, BCL2, and CASP9. RESULTS: JO-122(2) and TMZ monotherapy inhibited tumor growth (TGI = 42.08% and 61.44%, respectively). The combination therapy reduced tumor volume 4.9-fold compared to the vehicle control and achieved a TGI of 79.88% (p = 4.20 × 10⁻⁸ vs. control; p = 1.66 × 10⁻³ vs. TMZ; p = 5.97 × 10⁻⁵ vs. JO-122(2)). It also increased p53, Bax, and caspase-9 protein levels and decreased MDM2 and Bcl-2, with concordant upregulation of TP53 and BAX and downregulation of MDM2 and BCL2 mRNA, indicating modulation of the p53/MDM2/Bcl-2 axis. CONCLUSION: JO-122(2) exerts potent antitumor effects in GBM, particularly when combined with TMZ, by promoting mitochondrial apoptosis through the coordinated regulation of p53 and its downstream effectors.