CF101, an agonist to the A3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a colon carcinoma murine model.
NF-kappaB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor (A3AR), inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been shown to downregulate PKB/Akt and NF-kappaB protein expression level, we presumed that its combination with chemotherapy will enhance the antitumor effect of the cytotoxic drug. In this study, we utilized 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and a colon carcinoma xenograft model. It has been shown that a combined treatment of CF101 and 5-fluorouracil (5-FU) enhanced the cytotoxic effect of the latter on HCT-116 human colon carcinoma cell proliferation and tumor growth. Downregulation of PKB/Akt, NF-kappaB, and cyclin D1, and upregulation of caspase-3 protein expression level were observed in cells and tumor lesions on treatment with a combination of CF101 and 5-FU. Moreover, in mice treated with the combined therapy, myelotoxicity was prevented as was evidenced by normal white blood cell and neutrophil counts. These results show that CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.
Bar-Yehuda
Sara
S
Can-Fite BioPharma Ltd., Kiryat-Matalon, Petach-Tikva 49170, Israel.
Madi
Lea
L
Silberman
Daniel
D
Gery
Slosman
S
Shkapenuk
Maya
M
Fishman
Pnina
P
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D058909:Adenosine A3 Receptor Agonists; D000964:Antimetabolites, Antineoplastic; C478920:CF101; D000241:Adenosine; D005472:Fluorouracil
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