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Biomedical Journal
Volume 30, Issue 4 (9-2026)
IBJ 2026, 30(4): 225-233 |
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Kit O I, Maksimov A Y, Golovinov I V, Kuznetsova N S, Kaplieva I V, Khodakova D V, et al . Tropolone Derivative JO-122(2) Enhances Temozolomide Efficacy and p53-Mediated Apoptosis in Glioblastoma Xenografts. IBJ 2026; 30 (4) :225-233
URL: http://ibj.pasteur.ac.ir/article-1-5466-en.html
URL: http://ibj.pasteur.ac.ir/article-1-5466-en.html
Oleg I. Kit 
, Aleksey Yu. Maksimov , Igor V. Golovinov * , Natalia S. Kuznetsova , Irina V. Kaplieva , Daria V. Khodakova , Alexander B. Sagakyants , Anastasia V. Galina , Anna A. Shulga , Sofya V. Gurova , Elena S. Bondarenko , Eduard E. Rostorguev , Yurii A. Sayapin , Eugeny A. Gusakov
, Aleksey Yu. Maksimov , Igor V. Golovinov * , Natalia S. Kuznetsova , Irina V. Kaplieva , Daria V. Khodakova , Alexander B. Sagakyants , Anastasia V. Galina , Anna A. Shulga , Sofya V. Gurova , Elena S. Bondarenko , Eduard E. Rostorguev , Yurii A. Sayapin , Eugeny A. Gusakov
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.
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.
Type of Study: Full Length/Original Article |
Subject:
Cancer Biology
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