title: Tumor suppression by small molecule inhibitors of translation initiation.
abstract: Translation initiation factors are over-expressed and/or activated in many human cancers and may contribute to their genesis and/or progression. Removal of physiologic restraints on translation initiation causes malignant transformation. Conversely, restoration of physiological restrains on translation initiation reverts malignant phenotypes. Here, we extensively characterize the anti-cancer activity of two small molecule inhibitors of translation initiation: #1181, which targets the eIF2∙GTP∙Met-tRNAi ternary complex, and 4EGI-1, which targets the eIF4F complex. In vitro, both molecules inhibit translation initiation, abrogate preferentially translation of mRNAs coding for oncogenic proteins, and inhibit proliferation of human cancer cells. In vivo, both #1181 and 4EGI-1 strongly inhibit growth of human breast and melanoma cancer xenografts without any apparent macroscopic- or microscopic-toxicity. Mechanistically, #1181 phosphorylates eIF2α while 4EGI-1 disrupts eIF4G/eIF4E interaction in the tumors excised from mice treated with these agents. These data indicate that inhibition of translation initiation is a new paradigm in cancer therapy.
authors.affiliation: Harvard Medical School, USA.
authors.forename: Limo
authors.initials: L
authors.lastname: Chen
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: He
authors.forename: Rupam
authors.initials: R
authors.lastname: Sahoo
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Severine
authors.initials: S
authors.lastname: Denoyelle
authors.forename: Eihab
authors.initials: E
authors.lastname: Kabha
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yang
authors.forename: Revital Yefidoff
authors.initials: RY
authors.lastname: Freedman
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D006835:Hydrazones; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009574:Nitro Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: C517852:4EGI-1 compound; D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D039562:Eukaryotic Initiation Factor-4F; D006835:Hydrazones; D007211:Indoles; D009574:Nitro Compounds; D012333:RNA, Messenger; D013844:Thiazoles