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Combined Treatment with Evogliptin and Temozolomide Alters miRNA Expression but Shows Limited Additive Effect on
Seung Yoon Song1, Keun Soo Lee2, Jung Eun Lee1
1Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Republic of Korea.
Abstract:
Dipeptidyl-peptidase IV (DPP4) inhibitors have shown potential anti-tumor properties. This study investigates the therapeutic potential of evogliptin, a DPP4 inhibitor, both as a single agent and in combination with temozolomide (TMZ), in glioma models. In vitro studies were performed using U87 and U373 glioma cell lines exposed to different concentrations of TMZ (250, 500 μM) and evogliptin (250, 500 ng/mL), either alone or together, for 24, 48, and 72 h. Cell viability was determined with the MTT assay. In vivo effectiveness was tested in a xenograft mouse model treated with intraperitoneal injections of evogliptin (60 mg/k g/day), TMZ (15 mg/kg/day), or their combination over 3 weeks. The combination of TMZ and evogliptin markedly reduced cell viability compared to single-agent treatments. DPP4 mRNA levels decreased more substantially with combination therapy. miRNA expression profiling with Affymetrix arrays indicated that certain miRNAs, such as miR-4440 and miR-6780b-5p, were upregulated after treatment with evogliptin or the combination regimen, whereas others were downregulated. These miRNAs could play a role in limiting glioma growth through DPP4 regulation. In the animal model, evogliptin alone did not provide a survival advantage. Analysis of TCGA data showed that glioma patients with decreased DPP4 expression had improved survival rates. The co-administration of evogliptin and temozolomide resulted in distinct miRNA profile changes. Nevertheless, both in vitro and in vivo, the added cytotoxicity from the combination was minimal.
Insights
Evogliptin, a DPP4 inhibitor, combined with temozolomide showed reduced glioma cell viability in vitro but minimal added cytotoxicity in vivo. Glioma patients with lower DPP4 expression had better survival rates.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Dipeptidyl-peptidase IV (DPP4) inhibitors exhibit potential anti-tumor effects.
- Gliomas are aggressive brain tumors with limited treatment options.
Purpose of the Study:
- To evaluate the therapeutic potential of evogliptin, a DPP4 inhibitor, as a single agent and in combination with temozolomide (TMZ) in glioma models.
- To investigate the effects of this combination on cell viability, DPP4 mRNA levels, and miRNA expression.
Main Methods:
- In vitro studies using U87 and U373 glioma cell lines treated with varying concentrations of evogliptin and TMZ.
- In vivo efficacy assessment in a glioma xenograft mouse model.
- Cell viability assays (MTT), DPP4 mRNA analysis, and miRNA expression profiling (Affymetrix arrays).
- TCGA data analysis for patient survival correlation with DPP4 expression.
Main Results:
- The combination of TMZ and evogliptin significantly reduced glioma cell viability in vitro compared to single agents.
- Combination therapy led to a more substantial decrease in DPP4 mRNA levels.
- Distinct miRNA expression profiles were observed with combination treatment, with some miRNAs upregulated and others downregulated.
- Evogliptin alone did not improve survival in the animal model, and the combination showed minimal added cytotoxicity in vivo.
- TCGA data indicated improved survival in glioma patients with decreased DPP4 expression.
Conclusions:
- While evogliptin and TMZ combination shows promise in reducing glioma cell viability in vitro, its in vivo efficacy and added cytotoxicity are minimal.
- DPP4 expression levels correlate with glioma patient survival.
- Specific miRNAs modulated by evogliptin and TMZ may play a role in glioma growth regulation via DPP4.
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