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Decreased APE-1 by Nitroxoline Enhances Therapeutic Effect in a Temozolomide-resistant Glioblastoma: Correlation with
Hye Rim Cho1,2, Nisha Kumari1, Nishant Thakur1
1Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Abstract:
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival rates. The current standard treatment includes chemotherapy with temozolomide (TMZ), but acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. The purpose of our study was to investigate therapeutic effects of nitroxoline (NTX) against TMZ-resistant GBM in vitro and in vivo in TMZ-resistant GBM-bearing mouse model, which was correlated with diffusion-weighted imaging (DWI). For in vitro study, we used TMZ-resistant GBM cell lines and evaluated therapeutic effects of NTX by clonogenic and migration assays. Quantitative RT-PCR was used to investigate the expression level of TMZ-resistant genes after NTX treatment. For in vivo study, we performed 9.4 T MR imaging to obtain T2WI for tumor volume measurement and DWI for assessment of apparent diffusion coefficient (ADC) changes by NTX in TMZ-resistant GBM mice (n = 8). Moreover, we performed regression analysis for the relationship between ADC and histological findings, which reflects the changes in cellularity and apurinic/apyrimidinic endonuclease-1 (APE-1) expression. We observed the recovery of TMZ-induced morphological changes, a reduced number of colonies and a decreased rate of migration capacity in TMZ-resistant cells after NTX treatment. The expression of APE-1 was significantly decreased in TMZ-resistant cells after NTX treatment compared with those without treatment. In an in vivo study, NTX reduced tumor growth in TMZ-resistant GBM mice (P = 0.0122). Moreover, ADC was increased in the NTX-treated TMZ-resistant GBM mice compared to the control group (P = 0.0079), which was prior to a tumor volume decrease. The cellularity and APE-1 expression by histology were negatively correlated with the ADC value, which in turn resulted in longer survival in NTX group. The decreased expression of APE-1 by NTX leads to therapeutic effects and is inversely correlated with ADC in TMZ-resistant GBM. Therefore, NTX is suggested as potential therapeutic candidate against TMZ-resistant GBM.
Insights
Nitroxoline (NTX) shows therapeutic effects against temozolomide-resistant glioblastoma multiforme (GBM) by reducing tumor growth and APE-1 expression. This novel treatment strategy offers potential for improved outcomes in resistant GBM cases.
Area of Science:
- Oncology
- Neuro-oncology
- Radiology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Temozolomide (TMZ) resistance is a major challenge in GBM therapy.
- Novel therapeutic agents are needed to overcome TMZ resistance.
Purpose of the Study:
- To investigate the therapeutic potential of nitroxoline (NTX) against TMZ-resistant GBM.
- To evaluate NTX effects in vitro and in a preclinical in vivo model.
- To correlate imaging biomarkers with therapeutic response.
Main Methods:
- In vitro studies used TMZ-resistant GBM cell lines with clonogenic and migration assays.
- Quantitative RT-PCR assessed gene expression changes post-NTX treatment.
- In vivo studies utilized a mouse model with 9.4T MRI (T2WI and DWI) and histological analysis.
Main Results:
- NTX treatment reduced colony formation and migration in TMZ-resistant GBM cells.
- NTX significantly decreased APE-1 expression in vitro.
- In vivo, NTX reduced tumor growth and increased ADC values, correlating with decreased cellularity and APE-1 expression.
Conclusions:
- Nitroxoline demonstrates significant therapeutic efficacy against TMZ-resistant GBM.
- Decreased APE-1 expression and increased ADC are key indicators of NTX treatment response.
- NTX represents a promising therapeutic candidate for overcoming TMZ resistance in GBM.
