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

RICHARD SM; MARTINEZ MARIGNAC VERONICA; ANSELMINO, LUCIANO

Mar del Plata, Buenos Aires

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2016

Sociedad Argentina de Investigaciones Clínicas

The search of targeted therapy among drugs and compounds in clinical use for diseases others than cancer is an strategy of low cost and probable of fast track to phase I and clinical studies.In this regards, the repurposing of ribavirin, an antiviral with more than years of use in the clinic against several DNA and RNA viruses, in cancer has been proposed since it is a specific inhibitor of inositide5'monophosphate dehydrogenase (IMPDH) and an inhibitor of the eucaryotic translation initiation factor E (eiF4E) activity. IMPDH expression and activity as well as eiF4Eare deregulated in many cancers. Both metabolic and signalling pathways have been reported to have important roles in the development and progression of hematological malignancies and to be overexpressed in colorectal cancer. Objective: to study the effect of ribavirin on oxaliplatin, a commonly used drug in CRC therapy, in two commercially available cell lines HT29 and HCt166 by Sulforhodamine B cytotoxicity assays. Results:drug combination showed that a clinically achievable concentration of ribavirin (10uM) resulted in a significantly synergistic effect on oxaliplatin in both cell lines tested.Conclusions: we showed sensitization to oxaliplatin by targeting the cap dependent translation pathway using ribavirin. Our findings suggested that the metabolic changes induced by oxaliplatin were dependent on downstream of mTor/AKT pathway in particular mTor/eiF4E pathway in HT29 and HCT116 cell lines making eiF4E 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 where ribavirin has been reported as a reliable approach in therapy.