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

Kit, Oleg I.; Maksimov, Alexey Yu.; Golovinov, Igor V.; Kuznetsova, Natalia S.; Kaplieva, Irina V.; Khodakova, Daria V.; Sagakyants, Alexander B.; Galina, Anastasia V.; Shulga, Anna A.; Gurova, Sofya V.; Bondarenko, Elena S.; Rostorguev, Eduard E.; Sayapin, Yurii A.; Gusakov, Eugeny A.

doi:10.22034/IBJ.30.4.225

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

Document Type : Full Length/Original Article

Authors

Oleg I. Kit ¹

Alexey Yu. Maksimov ¹

Igor V. Golovinov ¹

Natalia S. Kuznetsova ¹

Irina V. Kaplieva ¹

Daria V. Khodakova ¹

Alexander B. Sagakyants ¹

Anastasia V. Galina ¹

Anna A. Shulga ¹

Sofya V. Gurova ¹

Elena S. Bondarenko ¹

Eduard E. Rostorguev ¹

Yurii A. Sayapin ²

Eugeny A. Gusakov ³

¹ Federal State Budgetary Institution "National Medical Research Centre for Oncology" of the Ministry of Health of the Russian Federation, Rostov-on-Don, Russian Federation

² 2Federal State Budgetary Institution of Science "Federal Research Centre Southern Scientific Centre of the Russian Academy of Sciences" (SSC RAS), Rostov-on-Don, Russian Federation

³ Research Institute of Physics and Chemistry, Southern Federal University, Rostov-on-Don, Russian Federation

10.22034/IBJ.30.4.225

Abstract

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.

Highlights

PMID: 42728353 PMCID: PMC13648291

Keywords

Glioblastoma

Temozolomide

Apoptosis

Tropolone

p53