Ribavirin and quercetin synergistically downregulate signal transduction and are cytotoxic in human ovarian carcinoma cells

Ribavirin, a nucleoside, well known as a broad-spectrum antiviral agent, is extensively used in the treatment of hepatitis C infections. Ribavirin inhibits IMP DH (EC 1.1.1.205) activity and reduces cellular GTP concentration. Quercetin, a plant flavonoid, exhibits antineoplastic activity and inhibits PI 4-kinase (EC 2.7.1.67) and PIP 5-kinase (EC 2.7.1.68) activity. Ribavirin and quercetin attack the cell cycle at the G(1) and G(1)/S boundary, respectively. Because they act on different enzyme targets and arrear the cell cycle at different phases, we tested the hypothesis that ribavirin and quercetin might be synergistic in growth inhibition and cytotoxicity. Human myeloma 8226 and human ovarian carcinoma OVCAR-5 cells were studied because in these cells IMP DH activity increased 14- and 20-fold, respectively, and PI 4- and PIP 5-kinase activities were also elevated. In growth inhibition for ribavirin and quercetin in myeloma 8226 cells IC(50)s were 40 and 70 mu M, respectively. In OVCAR-5 cells in growth inhibition and clonogenic assays for ribavirin IC50, and LC50 of 35 and 23 mu M, respectively, were observed. When quercetin was added 24 h after ribavirin, synergistic antiproliferative action was observed in both myeloma 8226 and OVCAR-5 cells. Synergistic action was also obtained in OVCAR-5 cells in clonogenic assay when ribavirin was combined with quercetin in the sequence described above. The mechanism of action is provided, in part at least, by the synergistic reduction of signal transduction (IP, concentration) by ribavirin and quercetin. Ribavirin and quercetin in combination might be of interest in the treatment of myeloma and ovarian carcinoma.