pateamine-a and hippuristanol

Covering: up to 2019Pharmacological targeting of eukaryotic mRNA translation initiation is a promising approach for cancer therapy, since several signaling pathways that are commonly deregulated during tumor progression converge on this process. The DEAD-box helicase, eukaryotic initiation factor (eIF) 4A, is essential for translation initiation and facilitates the loading of the 43S pre-initiation complex onto mRNAs. Hippuristanol, rocaglates, and pateamine A are natural products that each target eIF4A by interfering with the helicase's RNA-binding activity in distinct manners. They exert a selective change in gene expression that results in potent anti-tumorigenic activity in pre-clinical studies. This review will provide an update on the molecular mechanisms of action of these natural products.

Topics: Animals; Antineoplastic Agents; Biological Products; DEAD-box RNA Helicases; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Gene Expression Regulation; Humans; Macrolides; Molecular Targeted Therapy; Neoplasms; Protein Biosynthesis; Sterols; Thiazoles

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

The PI3K/Akt/mTOR kinase pathway is extensively deregulated in human cancers. One critical node under regulation of this signaling axis is eukaryotic initiation factor (eIF) 4F, a complex involved in the control of translation initiation rates. eIF4F-dependent addictions arise during tumor initiation and maintenance due to increased eIF4F activity-generally in response to elevated PI3K/Akt/mTOR signaling flux. There is thus much interest in exploring eIF4F as a small molecule target for the development of new anticancer drugs. The DEAD-box RNA helicase, eIF4A, is an essential subunit of eIF4F, and several potent small molecules (rocaglates, hippuristanol, pateamine A) affecting its activity have been identified and shown to demonstrate anticancer activity in vitro and in vivo in preclinical models. Recently, a number of new small molecules have been reported as having the capacity to target and inhibit eIF4A. Here, we undertook a comparative analysis of their biological activity and specificity relative to the eIF4A inhibitor, hippuristanol.

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Cell Survival; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factor-4F; Humans; Macrolides; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Small Molecule Libraries; Sterols; Thiazoles; TOR Serine-Threonine Kinases

Cachexia is a deadly muscle wasting syndrome that arises under conditions linked to chronic inflammation, such as cancer. Cytokines, including interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and their downstream effectors such as Signal Transducer and Activator of Transcription 3 (STAT3), have been shown to play a prominent role in muscle wasting. Previously, we demonstrated that Pateamine A (PatA), a compound that targets eukaryotic initiation factor 4A (eIF4A), could prevent muscle wasting by modulating the translation of the inducible Nitric Oxide Synthase (iNOS) mRNA. Here we show that hippuristanol, a compound that impedes eIF4A in a manner distinct from PatA, similarly inhibits the iNOS/NO pathway and cytokine-induced muscle wasting. Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3-gene targets such as IL-6. The decreased activation of STAT3, which resulted from a decrease in STAT3 protein expression, was due to the inhibition of STAT3 translation as there were no changes in STAT3 mRNA levels. These effects are likely dependent on the inhibition of eIF4A activity since we observed similar results using PatA. Our results identify the inhibition of eIF4A-responsive transcripts, such as STAT3, as a viable approach to alleviate cachexia.

Topics: Allosteric Regulation; Animals; Cell Line; Cytokines; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Interleukin-6; Macrolides; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; Nitric Oxide Synthase Type II; STAT3 Transcription Factor; Sterols; Thiazoles

The RNA helicases eIF4AI and eIF4AII play key roles in recruiting ribosomes to mRNA templates during eukaryotic translation initiation. Small molecule inhibitors of eIF4AI and eIF4AII have been useful for chemically dissecting their role in translation in vitro and in vivo. Here, we describe a screen performed on a small focused library of kinase inhibitors to identify a novel helicase inhibitor. We describe assays that have been critical for characterizing novel RNA helicase inhibitors.

Topics: Animals; Anthracenes; Benzofurans; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Humans; Macrolides; Perylene; Protein Kinase Inhibitors; Sterols; Thiazoles