Molecular pathways associated with antitumor activity of ribavirin (Riba)

5857 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 IC 50 = 15 uM at 120 hr (and IC 50 = 195 uM at 24 hr). Riba down-regulated signal transduction activity in a time- and dose-dependent fashion, as measured by IP 3 concentration. Early down-regulation was demonstrated for c-MYC (t 1/2 = 30 min), hTERT (t 1/2 = 1 hr), Ki-RAS (t 1/2 = 3 hr), and PI3K (t 1/2 = 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