The Anti-Tumor Effect of A3 Adenosine Receptors Is Potentiated by Pulsed Electromagnetic Fields in Cultured Neural Cancer Cells

Abstract

A3 adenosine receptors (ARs) play a pivotal role in the development of cancer and their activation is involved in the inhibition of tumor growth. The effects of pulsed electromagnetic fields (PEMFs) on cancer have been controversially discussed and the detailed mechanisms are not yet fully understood. In the past we have demonstrated that PEMFs increased A2A and A3AR density and functionality in human neutrophils, human and bovine synoviocytes, and bovine chondrocytes. In the same cells, PEMF exposure increased the anti-inflammatory effect mediated by A2A and/or A3ARs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-tumor effect of A3ARs in PC12 rat adrenal pheochromocytoma and U87MG human glioblastoma cell lines in comparison with rat cortical neurons. Saturation binding assays and mRNA analysis revealed that PEMF exposure up-regulated A2A and A3ARs that are well coupled to adenylate cyclase activity and cAMP production. The activation of A2A and A3ARs resulted in the decrease of nuclear factor-kappa B (NF-kB) levels in tumor cells, whilst only A3ARs are involved in the increase of p53 expression. A3AR stimulation mediated an inhibition of tumor cell proliferation evaluated by thymidine incorporation. An increase of cytotoxicity by lactate dehydrogenase (LDH) release and apoptosis by caspase-3 activation in PC12 and U87MG cells, but not in cortical neurons, was observed following A3AR activation. The effect of the A3AR agonist in tumor cells was enhanced in the presence of PEMFs and blocked by using a well-known selective antagonist. Together these results demonstrated that PEMF exposure significantly increases the anti-tumor effect modulated by A3ARs.

Pulsed Electromagnetic Fields Increased the Anti-Inflammatory Effect of A2A and A3 Adenosine Receptors in Human T/C-28a2 Chondrocytes and hFOB 1.19 Osteoblasts

“…The treatment with PEMFs induced a selective increase in A 2A ARs expressed in rat cortex membranes and in rat cortical neurons [30]. A potentiated anti-tumoral effect of A 3 ARs by PEMFs was found in different cell lines such as rat adrenal pheochromocytoma (PC12) and human glioblastoma (U87MG) cell lines [31]. A role of ARs and PEMFs in modulating bovine chondrocytes and synoviocytes activity has been previously documented [32], [33].…”

A2A Adenosine Receptors Are Differentially Modulated by Pharmacological Treatments in Rheumatoid Arthritis Patients and Their Stimulation Ameliorates Adjuvant-Induced Arthritis in Rats

“…LDH assay was performed in human lymphocytes from untreated RA patients as previously described [35]. At the end of incubation with CGS 21680 for 24 hours, 100 µl of supernatant per well was harvested and transferred into a new 96-well, flat-bottom plate.…”

Purinergic signalling and cancer

“…Modulation of metalloproteinase-9 in U87MG cells via A 3 receptors has been reported [630]. Pulsed electromagnetic field exposure significantly increased the anti-tumour effect mediated by A 3 receptors in a human glioblastoma cell line [631]. Data have been presented to suggest that A 3 receptor agonists may be potential therapeutic agents for the induction of apoptosis in human glioma cells [632].…”