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Ribavirin (Riba), an antiviral agent, exerts antitumor activity in sensitive cells through inhibiting IMP dehydrogenase (EC 1.1.1.205) activity and reducing GTP concentration (Weber et al., Advan. Enzyme Regul. 43: 47-56, 2003). In previous studies we demonstrated a marked growth inhibition by Riba in various human cancer cells. To elucidate the involvement of key signaling pathways, in the present study the effect of Riba on gene expression was examined by using quantitative real-time PCR and oligonucleotide microarrays. In human leukemia K-562 cells Riba in growth inhibition studies yielded IC50 = 15 uM at 120 hr (and IC50 = 195 uM at 24 hr). Riba down-regulated signal transduction activity in a time- and dose-dependent fashion, as measured by IP3 concentration. Early down-regulation was demonstrated for c-MYC (t1/2 = 30 min), hTERT (t1/2 = 1 hr), Ki-RAS (t1/2 = 3 hr), and PI3K (t1/2 = 6 hr). A 3-fold up-regulation of the apoptosis pathway, measured by BAX/BCL-2 ratio was observed between 30 min and 2 hr. Riba (15 uM-195 uM) induced up to 8-fold increase in differentiation measured by hemoglobin synthesis, yielding up to 82% of benzidine-positive cells at 120 hr. Using oligonucleotide microarrays we examined the expression of 41,000 genes and transcripts. Treatment with Riba (15 uM) had a marked impact, resulting in early (30 min) modulation of expression of approximately 2000 genes (at p < 0.01). In addition to modulation of genes of RTK-, PI3K-, and apoptosis-pathway by Riba, as identified by RT-PCR, many genes were up-regulated, including stress response, differentiation, and apoptosis. Equal number of genes were down-regulated, including those associated with cell cycle regulation, protein synthesis and other biosynthetic functions. The data are confirmed by RT-PCR. These results suggest that Ribavirin should be effective against various tumor cells by interfering with the key signaling pathways. Supported by Hungarian Research Grant OTKA T046570 to E.O., and by a Grant from the Ladies Auxiliary of the Veterans of Foreign Wars, Indiana Division to G.W.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]