Adenosine acts as a chemoprotective agent by stimulating G-CSF production: A role for A1 and A3 adenosine receptors

Abstract

Adenosine, a ubiquitous nucleoside, is released into the extracellular environment from metabolically active or stressed cells. It binds to cells through specific A1, A(2A), A(2B), and A3 G-protein-associated cell-surface receptors, thus acting as a signal-transduction molecule by regulating the levels of adenylyl cyclase and phospholipase C. In this study, we showed that adenosine stimulates the proliferation of murine bone marrow cells in vitro. Pharmacological studies, using antagonists to the adenosine receptors, revealed that this activity was mediated through the binding of adenosine to its A1 and A3 receptors. This result was further corroborated by showing that the two selective A1 and A3 receptor agonists, N-cyclopentyladenosine (CPA) and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA) respectively, induced bone marrow cell proliferation in a manner similar to adenosine. Adenosine's interaction with its A1 and A3 receptors induced G-CSF production, which led to its stimulatory effect on bone marrow cells. These results were confirmed in vivo when we demonstrated that low-dose adenosine (0.25 mg/kg) acted as a chemoprotective agent. When administered after chemotherapy, it restored the number of leukocytes and neutrophils to normal levels, compared with the decline in these parameters after chemotherapy alone. It is suggested that low-dose adenosine, already in clinical use, may also be applied as a chemoprotective agent.

A3 Adenosine Receptor Activation Inhibits Cell Proliferation via Phosphatidylinositol 3-Kinase/Akt-dependent Inhibition of the Extracellular Signal-regulated Kinase 1/2 Phosphorylation in A375 Human Melanoma Cells

“…different mechanisms through which A 3 adenosine receptors are able to inhibit cell proliferation was found to involve inhibition of telomerase activity and a cell cycle arrest in the G 0 /G 1 phase, leading to a cytostatic effect (7,13,14). Furthermore, it has been demonstrated that the antigrowth signal exerted by A 3 receptors blocks cells into G 1 -late cell cycle phase (9).…”

Animal models for the study of adenosine receptor function

“…The A3 adenosine receptor can activate ERK1/2 in human fetal astrocytes. Moreover, A3 receptor activation has been implicated in inhibition of tumor growth both in vitro and in vivo (Fishman et al, 2000a(Fishman et al, ,b, 2001Bar-Yehuda et al, 2001;Ohana et al, 2001). Interestingly, attempts to overexpress the A3AR in a transgenic mouse model resulted in embryonic lethality (Zhao et al, 2002).…”

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

“…Current therapy is far from being uniformly useful to patients and not without side effects, thus limiting the appropriate dosage and duration of chemotherapy. The stimulatory effect of CF101 on bone marrow cell proliferation was mediated via the induction of G-CSF production (Fishman et al, 2000aBar-Yehuda et al, 2002). Thus, it became apparent that the A3AR might serve as a target for anticancer and myeloprotective treatments.…”