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.