pateamine-a and Neoplasms

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 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

Marine sponges are an excellent source of bioactive secondary metabolites with potential therapeutic value in the treatment of diseases. One group of compounds of particular interest is the microtubule-stabilizing agents, the most well-known compound of this group being paclitaxel (Taxol), an anti-cancer compound isolated from the bark and leaves of the Pacific yew tree. This review focuses on two of the more recent additions to this important class of drugs, peloruside A and zampanolide, both isolated from marine sponges. Peloruside A was isolated from Mycale hentscheli collected in New Zealand coastal waters, and it already shows promising anti-cancer activity. Two other potent bioactive compounds with different modes of action but isolated from the same sponge, mycalamide A and pateamine, will also be discussed. The fourth compound, zampanolide, most recently isolated from the Tongan sponge Cacospongia mycofijiensis, has only recently been added to the microtubule-stabilizing group of compounds, and further work is in progress to determine its activity profile relative to peloruside A and other drugs of this class.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Epoxy Compounds; Humans; Lactones; Macrolides; Microtubules; Neoplasms; Porifera; Pyrans; Thiazoles

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 natural product pateamineA (PatA) is a highly potent antiproliferative agent. PatA and the simplified analog desmethyl, desamino pateamineA (DMDAPatA) have exhibited cytotoxicity selective for rapidly proliferating cells, and have been shown to inhibit cap-dependent translation initiation through binding to eIF4A (eukaryotic initiation factor 4A) of the eIF4F complex. PatA and DMDAPatA are both known to stimulate the RNA-dependent ATPase, and ATP-dependent RNA helicase activities of eIF4A. The impact of other eIF4F components, eIF4E and eIF4G, on DMDAPatA action were investigated in vitro and in cultured mammalian cells. The perturbation of the eIF4A-eIF4G association was found to be eIF4E- and mRNA cap-dependent. An inhibitory effect on helicase activity of eIF4A was observed when it was part of a complex that mimicked the eIF4F complex. We propose a model of action for DMDAPatA (and by supposition PatA) where the cellular activity of the compound is dependent on an "active" eIF4F complex.

Topics: Adenosine Triphosphatases; Biological Products; Cell Line; Cell Proliferation; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Humans; Macrolides; Neoplasms; Recombinant Proteins; RNA, Messenger; Thiazoles

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

We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Epoxy Compounds; Female; Humans; Macrolides; Mice; Mice, Nude; Mice, SCID; Neoplasms; Thiazoles; Xenograft Model Antitumor Assays