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Purinergic approach to effective glioma treatment with temozolomide reveals enhanced anti-cancer effects mediated by
Bartosz Szymczak1, Joanna Czarnecka1, Sylwia Czach2
1Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Lwowska 1, 87-100 Torun, Poland.
Abstract:
The purinergic signaling pathway is the oldest evolutionary transmitter system that regulates a wide array of physiological and pathophysiological processes in central nervous system. However, the question of how the purinergic compounds interact with administrated drugs is rarely addressed. We aimed to clarify the interplay between purinergic signaling and chemotherapeutic drug temozolomide (TMZ) in human glioma cell line. We applied an initial retinoic acid-induced differentiation of A172 glioma cells and tested the P2X7 receptor expression in undifferentiated and differentiated gliomas. We compared the P2X7 receptor agonists/antagonists influence and their co-action with TMZ in both cell types through assessment of cell proliferation, viability and migrative properties. Molecular docking allowed to indicate the potential binding site for TMZ in the structure of hP2X7 receptor. Differentiated cells turned out to be more susceptible to ATP and TMZ alone but also to the concerted action of TMZ and ATP. Enhanced effects triggered by ATP and TMZ treatment include the decreased by 70% viability, and reduced migration ability of differentiated A172 glioma cells. Noteworthy, these results can be achieved already at low non-toxic ATP concentration and at reduced to 125 μM effective concentration of TMZ. Therefore, ATP molecules must be present and maintained at appropriate concentration in glioma cells microenvironment to achieve their co-action with TMZ and enhanced anti-cancer activity. All that, in turn, could shorten the therapy, increase its efficacy and limit the side effects for the patient. Our purinergic approach creates a promising perspective for developing novel combined oncological therapies.
Insights
Purinergic signaling, involving ATP, enhances chemotherapy effectiveness against glioma. Differentiated glioma cells showed reduced viability and migration when treated with ATP and temozolomide (TMZ).
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Purinergic signaling regulates numerous physiological and pathophysiological processes in the central nervous system.
- The interaction between purinergic compounds and chemotherapeutic drugs is not well understood.
- Gliomas are a type of brain tumor with significant treatment challenges.
Purpose of the Study:
- To investigate the interplay between purinergic signaling and temozolomide (TMZ) in human glioma cells.
- To assess the role of P2X7 receptor in the response to TMZ and purinergic compounds.
- To explore novel combination therapies for glioma treatment.
Main Methods:
- Retinoic acid-induced differentiation of A172 human glioma cells.
- Assessment of P2X7 receptor expression in undifferentiated and differentiated cells.
- Evaluation of cell proliferation, viability, and migration under various treatment conditions (ATP, TMZ, combined).
- Molecular docking to predict the binding site of TMZ in the P2X7 receptor.
Main Results:
- Differentiated glioma cells exhibited increased susceptibility to ATP and TMZ alone, and in combination.
- Combined ATP and TMZ treatment significantly decreased viability by 70% and reduced migration in differentiated A172 cells.
- Effective co-action was observed at low, non-toxic ATP concentrations and reduced TMZ concentrations (125 μM).
- Molecular docking suggested a potential binding site for TMZ within the human P2X7 receptor structure.
Conclusions:
- ATP is crucial for enhancing the anti-cancer activity of TMZ in glioma cells.
- The purinergic approach offers a promising strategy for developing novel, more effective combination therapies for glioma.
- Optimizing ATP concentration in the tumor microenvironment could improve TMZ efficacy and reduce patient side effects.
