Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy

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.

The Adenosine A1 Receptor Antagonist DPCPX Inhibits Tumor Progression via the ERK/JNK Pathway in Renal Cell Carcinoma

“…Previous studies have indicated that the activation of A1R may be associated with the ERK/JNK pathway. A1R agonist induced the phosphorylation of ERK/JNK, while its antagonist could inhibit the phosphorylation [19, 28, 29]. Our results are consistent with these previously published reports, suggesting that DPCPX may inhibit tumor progression in part via the ERK/JNK pathway (Fig.…”

“…In contrast, several studies also showed that the A1R antagonists could reduce cell proliferation [13, 18]. Notably, a combined treatment with A1R agonist and temozolomide significantly inhibited cell proliferation and promoted apoptosis compared to temozolomide alone in cancer stem cells [19], whereas A1R antagonist DPCPX was found to significantly induce apoptosis in MCF-7 cells [18]. In this study, the expression of A1R was up-regulated; thus, the A1R antagonist DPCPX was used.…”

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells

“…A 1 R activation inhibits proliferation in human metastatic cell line, and A 2A R activation promotes human melanoma cell death [50,51]. AdoR activation also has been shown to sensitize glioma cells to chemotherapic cytotoxic effects [52,53]. In this way, it has been already described that AdoR activation is capable of modulating apoptotic pathways in colorectal cancer, hepatocellular carcinoma, osteosarcoma, and lung cancer, for example, increasing BAX and BAD levels, promoting alteration in mitochondrial membrane potential and increasing the efflux of cytochrome C and triggering apoptosis [45].…”

Damage-associated molecular patterns in cancer: a double-edged sword

“…Noteworthy, adenosine, resulting from ATP hydrolysis by the ectoenzymes CD73 and CD39 exerts effect that are often opposite to those of ATP (see details in previous section), such as the promotion of an immunosuppressive environment via A2A receptors 76, 116, 117 as well as chemotaxis and metastasis via A2B receptors 79 . However, adenosine can also induce tumor cell death, via A1, A2A, A2B and A3 receptors 19118 , thereby additionally contributing to limit tumor growth (Fig 2). Therefore, the kinetics of ATP release and conversion to adenosine, as well as the large number of receptors for ATP and adenosine need to be taken into consideration when targeting this system for ICD induction.…”