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Journal Article

Marine natural products as anticancer drugs

01 Feb 2005-Molecular Cancer Therapeutics (American Association for Cancer Research)-Vol. 4, Iss: 2, pp 333-342
TL;DR: This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
Abstract: The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
Citations
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Journal ArticleDOI
TL;DR: This review covers the literature published in 2014 for marine natural products, with 1116 citations referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms.

4,649 citations

Journal ArticleDOI
TL;DR: The ecology of sponge-microbe associations is examined, including the establishment and maintenance of these sometimes intimate partnerships, the varied nature of the interactions (ranging from mutualism to host-pathogen relationships), and the broad-scale patterns of symbiont distribution.
Abstract: Marine sponges often contain diverse and abundant microbial communities, including bacteria, archaea, microalgae, and fungi. In some cases, these microbial associates comprise as much as 40% of the sponge volume and can contribute significantly to host metabolism (e.g., via photosynthesis or nitrogen fixation). We review in detail the diversity of microbes associated with sponges, including extensive 16S rRNA-based phylogenetic analyses which support the previously suggested existence of a sponge-specific microbiota. These analyses provide a suitable vantage point from which to consider the potential evolutionary and ecological ramifications of these widespread, sponge-specific microorganisms. Subsequently, we examine the ecology of sponge-microbe associations, including the establishment and maintenance of these sometimes intimate partnerships, the varied nature of the interactions (ranging from mutualism to host-pathogen relationships), and the broad-scale patterns of symbiont distribution. The ecological and evolutionary importance of sponge-microbe associations is mirrored by their enormous biotechnological potential: marine sponges are among the animal kingdom's most prolific producers of bioactive metabolites, and in at least some cases, the compounds are of microbial rather than sponge origin. We review the status of this important field, outlining the various approaches (e.g., cultivation, cell separation, and metagenomics) which have been employed to access the chemical wealth of sponge-microbe associations.

1,262 citations

Journal ArticleDOI
TL;DR: The main natural compounds used in cancer therapy and prevention, the historical aspects of their application and pharmacognosy, and some critical aspects of current cancer chemotherapy are discussed, focusing on genetics and genomics.

623 citations


Cites background from "Marine natural products as anticanc..."

  • ...Neovastat inhibits the binding of VEGF to its receptor [19,20]....

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  • ...salinosporamide hat inhibits proteasome or neovastat that blocks the vascular ndothelial growth factor (VEGF) binding to its receptor) [19,20]....

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  • ...[19] Simmons TL, Andrianasolo E, McPhail K, Flatt P, Gerwick WH....

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Journal ArticleDOI
TL;DR: Semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects.
Abstract: Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as “lead” compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

617 citations


Cites background from "Marine natural products as anticanc..."

  • ...This area of research, which is continually expanding and is of enormous current interest, explores new natural products coming from different sources, among which the sea could be quoted as an almost infinite source of resources [12–19], with a view to collecting more potent, more selective and less toxic compounds than today’s drugs, and hence with better therapeutic indices....

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Journal ArticleDOI
TL;DR: The full sequencing and functional expression of a marine natural-product pathway from an obligate symbiont is presented, and a related cluster was identified in Trichodesmium erythraeum IMS101, an important bloom-forming cyanobacterium.
Abstract: Prochloron spp. are obligate cyanobacterial symbionts of many didemnid family ascidians. It has been proposed that the cyclic peptides of the patellamide class found in didemnid extracts are synthesized by Prochloron spp., but studies in which host and symbiont cells are separated and chemically analyzed to identify the biosynthetic source have yielded inconclusive results. As part of the Prochloron didemni sequencing project, we identified patellamide biosynthetic genes and confirmed their function by heterologous expression of the whole pathway in Escherichia coli. The primary sequence of patellamides A and C is encoded on a single ORF that resembles a precursor peptide. We propose that this prepatellamide is heterocyclized to form thiazole and oxazoline rings, and the peptide is cleaved to yield the two cyclic patellamides, A and C. This work represents the full sequencing and functional expression of a marine natural-product pathway from an obligate symbiont. In addition, a related cluster was identified in Trichodesmium erythraeum IMS101, an important bloom-forming cyanobacterium.

536 citations

References
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Journal ArticleDOI
02 Apr 2004-Science
TL;DR: Over 1.2 million previously unknown genes represented in these samples, including more than 782 new rhodopsin-like photoreceptors are identified, suggesting substantial oceanic microbial diversity.
Abstract: We have applied “whole-genome shotgun sequencing” to microbial populations collected en masse on tangential flow and impact filters from seawater samples collected from the Sargasso Sea near Bermuda. A total of 1.045 billion base pairs of nonredundant sequence was generated, annotated, and analyzed to elucidate the gene content, diversity, and relative abundance of the organisms within these environmental samples. These data are estimated to derive from at least 1800 genomic species based on sequence relatedness, including 148 previously unknown bacterial phylotypes. We have identified over 1.2 million previously unknown genes represented in these samples, including more than 782 new rhodopsin-like photoreceptors. Variation in species present and stoichiometry suggests substantial oceanic microbial diversity. Microorganisms are responsible for most of the biogeochemical cycles that shape the environment of Earth and its oceans. Yet, these organisms are the least well understood on Earth, as the ability to study and understand the metabolic potential of microorganisms has been hampered by the inability to generate pure cultures. Recent studies have begun to explore environ

4,210 citations


"Marine natural products as anticanc..." refers background in this paper

  • ...By contrast, open ocean waters are generally low in nutrients and have been likened to deserts in terms of biomass and species diversity, although recent evidence suggests the existence of substantial microbial diversity in pelagic waters (1)....

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Journal ArticleDOI
TL;DR: From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well, and in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame.
Abstract: This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are bas...

2,985 citations


"Marine natural products as anticanc..." refers background in this paper

  • ...This has occurred in part during a period of some retrenchment in the field of natural products in general and may cause some to rethink the wisdom of prematurely departing from this highly productive pursuit (4)....

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Journal ArticleDOI
TL;DR: There are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase II/III clinical trials in cancer, analgesia, allergy, and cognitive diseases.
Abstract: The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in antitumor, antiinflammatory, analgesia, immunomodulation, allergy, and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase II/III clinical trials in cancer, analgesia, allergy, and cognitive diseases. A substantial number of other potential agents are following in their wake in preclinical trials in these and in other diseases.

705 citations


"Marine natural products as anticanc..." refers background in this paper

  • ...Therefore, current clinical evaluation of LU-103793 has been discontinued (53)....

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  • ...Phase II clinical trials in the United States and Europe continue for ovarian, STS, endometrial, breast, prostate, and non–small cell lung cancer, with notable recent success in combination drug therapy (53)....

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  • ...Large-scale collections, aquaculture and synthetic efforts have all been employed (53), and culminated in the development of a semisynthesis of ET-743 from cyanosafracin B (Fig....

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  • ...ILX-651 is currently in three phase II clinical trials for patients with locally advanced or metastatic non–small cell lung cancer and patients with hormone-refractory prostate cancer previously treated with Docetaxel (53).3 Results of a phase II study where ILX-651 was given daily for five consecutive days on a three week schedule in patients with inoperable locally advanced or metastatic melanoma indicate that it is ‘‘a safe, well-tolerated treatment for locally advanced and metastatic melanoma patients’’ (54)....

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  • ...The multifaceted mechanism of action of ET-743 includes interference with the cellular transcription-coupled nucleotide excision repair to induce cell death and cytotoxicity which is independent of p53 status yet occurs with multidrug resistance elicitation (53, 59)....

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Journal ArticleDOI
TL;DR: This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle and describes the natural and synthetic agents which are known to interact with tubulin.
Abstract: Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997. © 1998 John Wiley & Sons, Inc., Med Res Rev, 18, No. 4, 259–296, 1998.

624 citations