DRUG REPOSITIONING IN CANCER THERAPY: THE ANTIVIRAL RIBAVIRIN MODEL AND EIF4E INHIBITION.

RICHARD SM; ANSELMINO, LUCIANO; MARTINEZ MARIGNAC VERONICA L

MEDICINA (BUENOS AIRES)

MEDICINA (BUENOS AIRES)

Lugar: Buenos Aires; Año: 2016 vol. 76 p. 221 - 221

0025-7680

The search of targeted therapy among drugs and compoundsin clinical use for diseases others than cancer is an strategy oflow cost and probable of fast track to phase I and II clinical stud-ies. In this regards, the repurposing of Ribavirin, an antiviral withmore than 40 years of use in the clinic against several DNA andRNA viruses, in cancer has been proposed since it is a specificinhibitor of inositide5?monophosphate dehydrogenase (IMPDH)and an inhibitor of the eukaryotic translation initiation factor 4E(eIF4E) activity. IMPDH expression and activity as well as eIF4Eare deregulated in many cancers. Both metabolic and signallingpathways have been reported to have important roles in the de-velopment and progression of hematological malignancies and tobe overexpressed in colorectal cancer (CRC). Objective: to studythe effect of Ribavirin on Oxaliplatin, a commonly used drug inCRC therapy, in two commercially available cell lines (HT29 ndHCT116) by Sulforhodamine B (SRB) cytotoxicity assays. Results:drug combination showed that a clinically achievable concentrationof Ribavirin (10uM) resulted in a significantly synergistic effect onOxaliplatin in both cell lines tested with the sensitization index (R)of 2.93 ± 0.3 for HT29 and 1.71 ± 0.2 for HCT116, respectively.Conclusions: we showed sensitization to Oxaliplatin by targetingthe capdependent translation pathway using Ribavirin. Our find-ings suggested that the metabolic changes induced by Oxaliplatinwere dependent on downstream of PI3K/AKT pathway in particularmTOR/eIF4E pathway in HT29 and HCT116 cell lines makingeIF4E dependent translation a targetable pathway in CRC underthis treatment. More studies are needed in order to pursuit a phaseI clinical trial as it is the case in CML and CLL leukemia whereRibavirin has been reported as a reliable approach in therapy.