Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101.
Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A(2A), A(2B), and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, P<0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.
Ohana
G
G
Department of Surgery A/B, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine Tel-Aviv University, Petach-Tikva 49100, Israel.
Bar-Yehuda
S
S
Arich
A
A
Madi
L
L
Dreznick
Z
Z
Rath-Wolfson
L
L
Silberman
D
D
Slosman
G
G
Fishman
P
P
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002277:Carcinoma / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D058906:Purinergic P1 Receptor Agonists; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C478920:CF101; D058906:Purinergic P1 Receptor Agonists; D000241:Adenosine