Tumor suppression by small molecule inhibitors of translation initiation

• Published in: Oncotarget 2012-08, Vol.3 (8), p.869-881
• Main Authors: Chen, Limo, Aktas, Bertal H, Wang, Yibo, He, Xiaoying, Sahoo, Rupam, Zhang, Nancy, Denoyelle, Severine, Kabha, Eihab, Yang, Hongwei, Freedman, Revital Yefidoff, Supko, Jeffrey G, Chorev, Michael, Wagner, Gerhard, Halperin, Jose A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chemical Sciences; Eukaryotic Initiation Factor-2 - antagonists & inhibitors; Eukaryotic Initiation Factor-2 - metabolism; Eukaryotic Initiation Factor-4F - antagonists & inhibitors; Eukaryotic Initiation Factor-4F - metabolism; Female; Humans; Hydrazones; Indoles - pharmacokinetics; Indoles - pharmacology; Indoles - toxicity; Male; Medicinal Chemistry; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Mice; Mice, Nude; Nitro Compounds - pharmacokinetics; Nitro Compounds - pharmacology; Nitro Compounds - toxicity; Organic chemistry; Peptide Chain Initiation, Translational - drug effects; Phosphorylation; Protein Biosynthesis - drug effects; Research Papers; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Thiazoles - toxicity; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.598

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.