pateamine-a and silvestrol

The translation initiation factor eIF4E mediates a rate-limiting process that drives selective translation of many oncongenic proteins such as cyclin D1, survivin and VEGF, thereby contributing to tumour growth, metastasis and therapy resistance. As an essential regulatory hub in cancer signalling network, many oncogenic signalling pathways appear to converge on eIF4E. Therefore, targeting eIF4E-mediated cap-dependent translation is considered a promising anticancer strategy. This paper reviews the strategies that can be used to target eIF4E, highlighting agents that target eIF4E activity at each distinct level.

Topics: Animals; Antineoplastic Agents; Cyclin D1; Epoxy Compounds; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Macrolides; Neoplasms; Oligonucleotides, Antisense; Protein Biosynthesis; Ribavirin; RNA, Small Interfering; Signal Transduction; Sirolimus; Survivin; Thiazoles; Triterpenes; Vascular Endothelial Growth Factor A

The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5'-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.

Topics: Epoxy Compounds; Eukaryotic Initiation Factor-4A; Gene Expression Regulation, Neoplastic; Humans; Macrolides; Molecular Targeted Therapy; Neoplasms; Protein Biosynthesis; Protein Isoforms; Sterols; Thiazoles; Triterpenes

Deregulated translation initiation is implicated extensively in cancer initiation and progression. Several translation initiation factors cooperate with known oncogenes, are elevated in human tumors and have been implicated in drug resistance. Consequently, there is a great deal of interest in targeting this process to develop new chemotherapeutics, especially since clinical trial results have been mixed when targeting upstream pathways, such as the mammalian target of rapamycin. Several inhibitors have been characterized over the last 5 years that target the ribosome recruitment phase (eukaryotic initiation factor [eIF]4E [antisense oligonucleotides and 4EGI-1] or eIF4A [pateamine A, hippuristanol and silvestrol]), some of which demonstrate activity in preclinical cancer models. The promise of these inhibitors as chemotherapeutics highlights the importance of targeting this pathway and supports efforts aimed at identifying the most susceptible targets. In addition, the framework in which translation inhibitors would be best employed (i.e., as single agents or as adjuvant therapy) in the clinic remains to be explored systematically. Small-molecule inhibitors of translation initiation are validating the idea that protein synthesis is a legitimate target for curtailing tumor growth.

Topics: Antineoplastic Agents; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factor-4E; Humans; Hydrazones; Macrolides; Neoplasms; Nitro Compounds; Oligonucleotides, Antisense; Protein Biosynthesis; Sterols; Thiazoles; Triterpenes

Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.

Topics: A549 Cells; Antiviral Agents; Enzyme Inhibitors; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Humans; Influenza A virus; Macrolides; Protein Biosynthesis; Thiazoles; Triterpenes; Virus Replication