Iranian Biomedical Journal
مجله بیومدیکال ایران
IBJ
Basic Sciences
http://ibj.pasteur.ac.ir
1
admin
1028-852X
2008-823X
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10.22034
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8888
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en
jalali
1405
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gregorian
2026
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online
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fulltext
en
Tropolone Derivative JO-122(2) Enhances Temozolomide Efficacy and p53-Mediated Apoptosis in Glioblastoma Xenografts
Cancer Biology
Cancer Biology
مقاله کامل
Full Length/Original Article
<div style="text-align: justify;"><span style="font-family:Times New Roman;"><span style="font-size:11pt"><span style="line-height:normal"><b><span style="font-size:10.5pt"><span style="color:black">Background: </span></span></b><span style="font-size:10.5pt"><span style="color:black">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. </span></span></span></span><br>
<span style="font-size:11pt"><span style="line-height:normal"><b><span style="font-size:10.5pt"><span style="color:black">Methods</span></span></b><span style="font-size:10.5pt"><span style="color:black">: 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 <i>TP53</i>, <i>MDM2</i>, <i>BAX</i>, <i>BCL2</i>, and <i>CASP9</i>.</span></span></span></span><br>
<span style="font-size:11pt"><span style="line-height:normal"><b><span style="font-size:10.5pt"><span style="color:black">Results: </span></span></b><span style="font-size:10.5pt"><span style="color:black">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% (<i>p</i> = 4.20 × 10⁻⁸ vs. control; <i>p</i> = 1.66 × 10⁻³ vs. TMZ; <i>p</i> = 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 <i>TP53</i> and <i>BAX</i> and downregulation of <i>MDM2</i> and <i>BCL2</i> mRNA, indicating modulation of the p53/MDM2/Bcl-2 axis.</span></span></span></span><br>
<b><span style="font-size:10.5pt"><span style="line-height:115%"><span style="color:black">Conclusion: </span></span></span></b><span style="font-size:10.5pt"><span style="line-height:115%"><span style="color:black">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.</span></span></span></span></div>
Apoptosis, Glioblastoma, p53, Temozolomide, Tropolone
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http://ibj.pasteur.ac.ir/browse.php?a_code=A-10-6423-1&slc_lang=en&sid=1
Oleg I.
Kit
rnioi@list.ru