Ribavirin as a tri-targeted antitumor repositioned drug.
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.
Multidisciplinary Academic Division of Comalcalco, Juarez Autonomous University of Tabasco, Mexico.
Erick
E
De la Cruz-Hernandez
Faculty of Chemistry, Department of Pharmacy, National Autonomous University of Mexico, Mexico city, Mexico.
Jose Luis
JL
Medina-Franco
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Jaenai
J
Trujillo
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Alma
A
Chavez-Blanco
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Guadalupe
G
Dominguez-Gomez
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Enrique
E
Perez-Cardenas
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Aurora
A
Gonzalez-Fierro
Division of Basic Research, National Cancer Institute of Mexico, Mexico city, Mexico.
Lucia
L
Taja-Chayeb
Biomedical Research Institute, National Autonomous University of Mexico/National Cancer Institute of Mexico, Mexico city, Mexico.
Alfonso
A
Dueñas-Gonzalez
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003198:Computer Simulation; D058492:Drug Repositioning; D000071221:Enhancer of Zeste Homolog 2 Protein; D039561:Eukaryotic Initiation Factor-4E / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000187:drug effects; D006801:Humans; D007168:IMP Dehydrogenase / Q000187:drug effects* / Q000235:genetics; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000187:drug effects* / Q000235:genetics; D034741:RNA, Small Interfering; D012254:Ribavirin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D039561:Eukaryotic Initiation Factor-4E; D034741:RNA, Small Interfering; D012254:Ribavirin; D007168:IMP Dehydrogenase; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2