The A3 adenosine receptor as a new target for cancer therapy and chemoprotection.
Adenosine, a purine nucleoside, acts as a regulatory molecule, by binding to specific G-protein-coupled A(1), A(2A), A(2B), and A(3) cell surface receptors. We have recently demonstrated that adenosine induces a differential effect on tumor and normal cells. While inhibiting in vitro tumor cell growth, it stimulates bone marrow cell proliferation. This dual activity was mediated through the A3 adenosine receptor. This study showed that a synthetic agonist to the A3 adenosine receptor, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (Cl-IB-MECA), at nanomolar concentrations, inhibited tumor cell growth through a cytostatic pathway, i.e., induced an increase number of cells in the G0/G1 phase of the cell cycle and decreased the telomeric signal. Interestingly, Cl-IB-MECA stimulates murine bone marrow cell proliferation through the induction of granulocyte-colony-stimulating factor. Oral administration of Cl-IB-MECA to melanoma-bearing mice suppressed the development of melanoma lung metastases (60.8 +/- 6.5% inhibition). In combination with cyclophosphamide, a synergistic anti-tumor effect was achieved (78.5 +/- 9.1% inhibition). Furthermore, Cl-IB-MECA prevented the cyclophosphamide-induced myelotoxic effects by increasing the number of white blood cells and the percentage of neutrophils, demonstrating its efficacy as a chemoprotective agent. We conclude that A3 adenosine receptor agonist, Cl-IB-MECA, exhibits systemic anticancer and chemoprotective effects.
Fishman
P
P
Laboratory of Clinical and Tumor Immunology, Rabin Medical Center, Petach-Tikva, 49100, Israel. pfishman@post.tau.ac.il
Bar-Yehuda
S
S
Barer
F
F
Madi
L
L
Multani
A S
AS
Pathak
S
S
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D003520:Cyclophosphamide / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000517:prevention & control* / Q000628:therapy*; D009374:Neoplasms, Experimental; D011485:Protein Binding; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide