ABSTRACT
The inducible transcription factor nuclear factor-kappaB (NF-kappaB) plays an important role in the regulation of immune, inflammatory and carcinogenic responses. While normal NF-kappaB activation is necessary for cell survival and immunity, deregulated NF-kappaB expression is a characteristic phenomenon in cancer development, as well as in several inflammatory diseases. Hence, NF-kappaB has become a major target in drug discovery, and several natural and synthetic compounds have been investigated for their potential to inhibit NF-kappaB. Here, we discuss the applications of marine natural products, in particular, as novel, potent NF-kappaB inhibitors. With the oceans covering two-thirds of the Earth's surface, and with the uniqueness of the environmental properties of marine habitats, it is easily understandable that organisms thriving in the oceans constitute a rich source of chemically unique and biomedically powerful secondary metabolites. Since the early 1960s, significant effort has been placed on the pharmacological evaluation of marine secondary metabolites. Noteworthy achievements of this field of biomedically guided marine exploration, a scientific endeavour often referred to as the search for "Drugs from the Sea", include the discovery of numerous potent anti-cancer, anti-inflammatory, antimicrobial, and analgesic compounds. The chemical characteristics and molecular targets of marine NF-kappaB inhibitors discovered to date are presented and discussed in the context of marine chemical ecology.
Subject(s)
Biological Products/pharmacology , Marine Biology , NF-kappa B/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Biological Evolution , Ecology , Humans , NF-kappa B/physiology , Structure-Activity RelationshipABSTRACT
This review covers the applications of small-molecule and peptidic compounds isolated from marine organisms for biomedical research. Enzymes and proteins from marine sources are already on the market for biomedical applications, but the use of small-molecule biomedical research tools of marine origin is less developed. For many studies involving these molecules the ultimate goal is the application of small-molecule therapeutics in the clinic, but those that do not succeed in the clinic still have clearly defined biological activities, which may be of use as biomedical research tools. In other cases, the investigation of marine-derived compounds has led directly to the discovery of therapeutics with clinical applications. Both as tools and therapeutics, these small-molecule compounds are effective for investigating biological processes, and in this review the authors have chosen to concentrate on the ability of marine natural products to affect membrane processes, ion channels and intracellular processes.
Subject(s)
Biomedical Research , Marine Biology , Animals , Cell Membrane/drug effects , Humans , Ion Channels/drug effects , Peptides/isolation & purification , Peptides/pharmacologyABSTRACT
The inducible transcription factor nuclear factor kappaB (NF-kappaB) plays a central role in the regulation of immune, inflammatory and carcinogenic responses. While normal activation of NF-kappaB is required for cell survival and immunity, its deregulated expression is a characteristic of inflammatory and infectious diseases. In this study, we investigated the molecular mechanisms induced by lactones and chalcones isolated from Fijian kava (Piper methysticum) used in traditional medicine against urinary tract infections and asthma. In order to understand underlying regulatory mechanisms, inhibition of both NF-kappaB-driven reporter gene expression and TNFalpha-induced binding of NF-kappaB to a consensus response element was achieved at concentrations of 320 microM (flavokavain A), 175 microM (flavokavain B) and 870 microM (kavain and dihydrokavain). Moreover, kavain and flavokavains A and B treatment led to inhibition of both inhibitor of kappaB (IkappaB) degradation and subsequent translocation of p50 and p65 NF-kappaB subunits from the cytoplasm to the nucleus as shown by Western blot analysis. Additionally, kinase selectivity screening demonstrates that flavokavain A, but not kavain, nor flavokavain B, inhibits the IkappaB kinase (IKK) as well as PRAK (p38-regulated/activated kinase), MAPKAP-K3 (MAPK-activated protein kinase 3), DYRK1A (dual-specificity tyrosine-phosporylated and regulated kinase 1A) and Aurora B. Altogether, these results give a first insight into anti-inflammatory mechanisms triggered by traditionally used chemopreventive kava compounds.
Subject(s)
Gene Expression/drug effects , Kava/chemistry , NF-kappa B/metabolism , Plant Preparations/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Survival/drug effects , Cytoplasm/metabolism , Dose-Response Relationship, Drug , Electrophoretic Mobility Shift Assay , Genes, Reporter/drug effects , Humans , I-kappa B Kinase/metabolism , Luciferases/genetics , Molecular Structure , NF-kappa B/genetics , NF-kappa B p50 Subunit/metabolism , Plant Preparations/isolation & purification , Plant Roots/chemistry , Protein Transport , Transcription Factor RelA/metabolism , TransfectionABSTRACT
Phospholipases A(2) (PLA(2)s) form a family of enzymes catalyzing the hydrolysis of membrane phospholipids into arachidonic acid, which is the major precursor of pro-inflammatory eicosanoids. As a result, PLA(2)s have been considered as potential targets in anti-inflammatory drug discovery. Marine natural products are a rich source of bioactive compounds, including PLA(2) inhibitors. Here, we review the properties of marine PLA(2) inhibitors identified since the first discovery of PLA(2) inhibitory activity in the marine natural product manoalide in the mid 1980s.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Aquatic Organisms/chemistry , Biological Products/pharmacology , Phospholipase A2 Inhibitors , Terpenes/pharmacology , Animals , Diterpenes/pharmacology , Drug Discovery , Humans , Sesquiterpenes/pharmacologyABSTRACT
The deregulated activation of NF-kappaB is associated with cancer development and inflammatory diseases. With an aim to find new NF-kappaB inhibitors, we purified and characterized compounds from extracts of the Fijian sponge Rhabdastrella globostellata, the crinoid Comanthus parvicirrus, the soft corals Sarcophyton sp. nov. and Sinularia sp., and the gorgonian Subergorgia sp. after an initial screening of 266 extracts from different marine origins. Results obtained show that selected purified compounds had a cytotoxic effect on the human leukaemia cell line K562, inhibited both TNF-alpha-induced NF-kappaB-DNA binding as well as TNF-alpha-induced IkappaBalpha degradation and nuclear translocation of p50/p65. Furthermore, we observed the inhibition of NF-kappaB activation induced by an overexpression of IKKbeta. Interestingly, natural products inhibited IKKbeta kinase as well as the 26S proteasome proteolytic activity.
Subject(s)
Biological Products/pharmacology , Marine Biology , NF-kappa B/antagonists & inhibitors , Cell Line, Tumor , Humans , I-kappa B Proteins/chemistry , NF-KappaB Inhibitor alpha , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
The two naphthopyrones 6-methoxycomaparvin (1) and 6-methoxycomaparvin 5-methyl ether (2) were isolated from a bioactive methanol-soluble extract of the Fijian echinoderm Comanthus parvicirrus. Their structures were assigned on the basis of spectroscopic methods. X-ray diffraction analysis was used to confirm the structure of 1. Both compounds were tested for their potential to inhibit the activation of the transcription factor NF-kappaB, which plays an important role in cancer development and inflammation, and the mechanism of action of the two compounds was investigated. Both naphthopyrones 1 and 2 completely inhibit TNF-alpha-induced NF-kappaB activation at a concentration of 300 microM by inhibiting the enzymatic activity of the kinase IKKbeta.