RESUMO

The aim of the present study was to demonstrate that ribavirin, a known inhibitor of eIF4E and inosine 5'-phosphate dehydrogenase (IMPDH), also inhibits histone methyltransferase zeste homolog 2 (EZH2). A computational searching revealed that ribavirin has a high structural similarity to 3-deazaneplanocin A (DZNep). The growth inhibitory effects of ribavirin as well as its effects upon epigenetic enzymes were evaluated in various cancer cell lines. siRNA assays were used to downregulate eIF4E, EZH2 and IMPDH to determine the contribution of these targets to the growth inhibitory effects of ribavirin. Ribavirin decreased EZH2 expression, inhibited histone methyltransferase activity and decreased H3K27 trimethylation. Ribavirin induced variable growth inhibition in a number of cell lines and downregulation of the targets, EZH2, eIF4E and IMPDH1 and 2 by siRNA led to comparable growth inhibition while no significant further reduction in viability was observed when siRNA transfected cells were treated with ribavirin. The results showed that ribavirin inhibits these cancer targets and should thus be studied for cancer therapy.

Assuntos

Antineoplásicos/farmacologia , Antivirais/farmacologia , Proliferação de Células/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , IMP Desidrogenase/efeitos dos fármacos , Neoplasias/genética , Complexo Repressor Polycomb 2/efeitos dos fármacos , Ribavirina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Reposicionamento de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste , Fator de Iniciação 4E em Eucariotos/genética , Células HeLa , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Humanos , IMP Desidrogenase/genética , Células MCF-7 , Neoplasias/metabolismo , Complexo Repressor Polycomb 2/genética , RNA Interferente Pequeno