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Tinostamustine (EDO-S101) and Its Combination with Celecoxib or Temozolomide as a Therapeutic Option for Adult-Type
Wiktoria Pawlak1, Aleksandra Majchrzak-Celińska1
1Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland.
Abstract:
Adult-type diffuse gliomas are characterized by inevitable recurrence and very poor prognosis. Novel treatment options, including multimodal drugs or effective drug combinations, are therefore eagerly awaited. Tinostamustine is an alkylating and histone deacetylase inhibiting molecule with great potential in cancer treatment. Thus, the aim of this study was to investigate its effects on glioma cells. In this context, tinostamustine was evaluated in monotherapy and as a combination therapy, with either celecoxib or temozolomide; additionally, the results were compared to the golden glioma chemotherapy standard-temozolomide. Our experiments, conducted on both temozolomide-sensitive U-87 MG astrocytoma and temozolomide-resistant U-138 MG glioblastoma cells revealed that tinostamustine and its combination with either celecoxib or temozolomide exert dose-dependent cytotoxicity, cause cell cycle arrest, induce oxidative stress-mediated apoptosis of malignant glioma cells, and mitigate their migratory potential. Astrocytoma cells were more susceptible to the tested treatments than glioblastoma cells, and, generally, those dual therapies were superior in anti-glioma efficacy compared to temozolomide. Overall, our study provides evidence that tinostamustine and the combination therapies consisting of tinostamustine and celecoxib or tinostamustine and temozolomide may represent a new approach for the effective treatment of malignant gliomas.
Insights
Tinostamustine, a novel drug, shows promise in treating malignant gliomas. It effectively reduces glioma cell growth, induces cell death, and inhibits migration, especially in combination therapies.
Area of Science:
- Neuro-oncology
- Pharmacology
- Cancer Biology
Background:
- Adult-type diffuse gliomas have poor prognoses and high recurrence rates.
- New therapeutic strategies, including drug combinations, are urgently needed for glioma treatment.
- Tinostamustine, an alkylating and HDAC inhibiting agent, presents potential for cancer therapy.
Purpose of the Study:
- To evaluate the efficacy of tinostamustine as monotherapy and in combination with celecoxib or temozolomide against glioma cells.
- To compare tinostamustine-based therapies with temozolomide, the current standard chemotherapy for gliomas.
Main Methods:
- In vitro assessment of tinostamustine's effects on temozolomide-sensitive (U-87 MG) and temozolomide-resistant (U-138 MG) glioma cell lines.
- Evaluation of monotherapy and combination therapies (tinostamustine + celecoxib, tinostamustine + temozolomide).
- Assessment of cytotoxicity, cell cycle arrest, apoptosis induction, and migratory potential.
Main Results:
- Tinostamustine and its combinations demonstrated dose-dependent cytotoxicity and reduced migratory potential in glioma cells.
- Treatments induced cell cycle arrest and oxidative stress-mediated apoptosis in malignant glioma cells.
- Astrocytoma cells were more sensitive than glioblastoma cells; combination therapies generally outperformed temozolomide.
Conclusions:
- Tinostamustine exhibits significant anti-glioma activity in vitro.
- Combination therapies with tinostamustine (with celecoxib or temozolomide) show superior efficacy compared to temozolomide alone.
- Tinostamustine-based therapies represent a promising new strategy for treating malignant gliomas.
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