Abstract
Therapies that target the signal transduction and biological characteristics of cancer stem cells (CSCs) are innovative strategies that are used in combination with conventional chemotherapy and radiotherapy to effectively reduce the recurrence and significantly improve the treatment of glioblastoma multiforme (GBM). The two main strategies that are currently being exploited to eradicate CSCs are (a) chemotherapeutic regimens that specifically drive CSCs toward cell death and (b) those that promote the differentiation of CSCs, thereby depleting the tumour reservoir. Extracellular purines, particularly adenosine triphosphate, have been implicated in the regulation of CSC formation, but currently, no data on the role of adenosine and its receptors in the biological processes of CSCs are available. In this study, we investigated the role of adenosine receptor (AR) subtypes in the survival and differentiation of CSCs isolated from human GBM cells. Stimulation of A1AR and A2BAR had a prominent anti-proliferative/pro-apoptotic effect on the CSCs. Notably, an A1AR agonist also promoted the differentiation of CSCs toward a glial phenotype. The differential effects of the two AR agonists on the survival and/or differentiation of CSCs may be ascribed to their distinct regulation of the kinetics of ERK/AKT phosphorylation and the expression of hypoxia-inducible factors. Most importantly, the AR agonists sensitised CSCs to the genotoxic activity of temozolomide (TMZ) and prolonged its effects, most likely through different mechanisms, are as follows: (i) by A2BAR potentiating the pro-apoptotic effects of TMZ and (ii) by A1AR driving cells toward a differentiated phenotype that is more sensitive to TMZ. Taken together, the results of this study suggested that the purinergic system is a novel target for a stem cell-oriented therapy that could reduce the recurrence of GBM and improve the survival rate of GBM patients.
Highlights
Glioblastoma multiforme (GBM) and contribute to its highly proliferative nature, but to be the basis for its recurrences following treatment
The formation of neurospheres in vitro in U87MG and U343MG cell cultures was induced by using specific neural stem cell (NSC) medium[35] (Supplementary Figure 1A)
We found that purinergic receptors for adenosine, and the A1AR and A2BAR subtypes, had a pivotal role in the survival and/or differentiation of glioblastoma cancer stem cells (CSCs)
Summary
GBM and contribute to its highly proliferative nature, but to be the basis for its recurrences following treatment. It has been reported that the most aggressive or refractory cancers contain the highest number of CSCs.[4,5,6] These findings suggest that innovative stem cell-orientated therapy may be an effective strategy to reduce tumour recurrence and significantly improve GBM treatment outcomes.[7,8,9,10,11,12,13,14,15,16,17,18] This type of therapy may not be easy to implement because CSCs have been shown to have a low level of reactive oxygen species[19] and to be more resistant to ionising radiation,[20] vincristine,[21] hypoxia and other chemotherapeutics[22] compared with non-CSCs. In contrast, the preferential elimination of the CSC population may contribute to the effectiveness of TMZ, which is the most effective pharmacologic agent used in glioma treatment;[23] the activity of TMZ appears to be short lived because the drug causes the reversible blockage of the cell cycle of CSCs.[24] long-term TMZ therapy results in the occurrence of drug-resistant GBM cells,[25] indicating the need to develop distinct strategies to overcome this resistance. Our data clarified the role of each AR subtype in CSC functionality and suggested that the purinergic system is a novel pharmacological target for the development of new anti-CSC therapies, those aimed at the treatment of GBM recurrences
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