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Mechanism of Action Analysis for Marine Compounds

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (30 November 2013) | Viewed by 34908

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Special Issue Editor

Dr. Paul Teesdale-Spittle

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Guest Editor

School of Biological Sciences, Victoria University of Wellington, Wellington 6140, New Zealand

Special Issue Information

Dear Colleagues,

The marine environment provides a wealth of structurally and functionally interesting molecules. Whilst these molecules include many with exquisite biological activity, determination of definitive mechanisms of action is challenging.
Assays employed during isolation of marine natural products often determine activity against one of more individual targets or against cellular systems. These approaches do not guarantee that any identified target is the sole, or even primary, mediator of the biological activity and only rarely are compounds studied in sufficient depth to identify the full scope of potential targets.
From a pharmaceutical perspective, unidentified targets can lead to unexpected activities including side effects and complex structure activity relationships. This issue is devoted to studies which assess or apply bioactivity profiling through high content screens to provide an in-depth analysis of the mechanisms of action of marine natural products or their analogues.

Dr. Paul Teesdale-Spittle
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

mechanism of action
high content screening
bioactivity profiling
chemogenomics
proteomics
chemical proteomics
transcriptomics
phenotypic analysis

Published Papers (4 papers)

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Research

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921 KiB

Open AccessArticle

Aplysin Sensitizes Cancer Cells to TRAIL by Suppressing P38 MAPK/Survivin Pathway

by Jia Liu, Leina Ma, Ning Wu, Ge Liu, Lanhong Zheng and Xiukun Lin

Mar. Drugs 2014, 12(9), 5072-5088; https://doi.org/10.3390/md12095072 - 25 Sep 2014

Cited by 28 | Viewed by 6885

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer and has been shown to be promising for treating various types of cancers. However, the application of TRAIL is greatly impeded by the resistance of cancer cells to its action. Studies show that overexpression of some critical pro-survival proteins, such as survivin, is responsible for TRAIL resistance. In this study, we found that Aplysin, a brominated compound from marine organisms, was able to restore the sensitivity of cancer cells to TRAIL both in vitro and in vivo. Aplysin was found to enhance the tumor-suppressing capacity of TRAIL on several TRAIL-resistant cancer cell lines. TRAIL-induced apoptosis was also potentiated in A549 and MCF7 cells treated with Aplysin. Survivin downregulation was identified as a mechanism by which Aplysin-mediated TRAIL sensitization of cancer cells. Furthermore, the activation of p38 MAPK was revealed in Aplysin-treated cancer cells, and its inhibitor SB203580 was able to abrogate the promoting effect of Aplysin on the response of cancer cells to TRAIL action, as evidenced by restored survivin expression, elevated cell survival and reduced apoptotic rates. In conclusion, we provided evidence that Aplysin acts as a sensitizer for TRAIL and its effect on p38 MAPK/survivin pathway may partially account for this activity. Considering its low cytotoxicity to normal cells, Aplysin may be a promising agent for cancer treatment in combination with TRAIL. Full article

(This article belongs to the Special Issue Mechanism of Action Analysis for Marine Compounds)

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1247 KiB

Open AccessArticle

Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production

by Caroline Ballot, Alain Martoriati, Manel Jendoubi, Sébastien Buche, Pierre Formstecher, Laurent Mortier, Jérome Kluza and Philippe Marchetti

Mar. Drugs 2014, 12(2), 779-798; https://doi.org/10.3390/md12020779 - 27 Jan 2014

Cited by 37 | Viewed by 8036

Abstract

Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents. Full article

(This article belongs to the Special Issue Mechanism of Action Analysis for Marine Compounds)

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813 KiB

Open AccessArticle

Continuous Drug Release by Sea Anemone Nematostella vectensis Stinging Microcapsules

by Yossi Tal, Ari Ayalon, Agnesa Sharaev, Zoya Kazir, Vera Brekhman and Tamar Lotan

Mar. Drugs 2014, 12(2), 734-745; https://doi.org/10.3390/md12020734 - 27 Jan 2014

Cited by 8 | Viewed by 7387

Abstract

Transdermal delivery is an attractive option for drug delivery. Nevertheless, the skin is a tough barrier and only a limited number of drugs can be delivered through it. The most difficult to deliver are hydrophilic drugs. The stinging mechanism of the cnidarians is a sophisticated injection system consisting of microcapsular nematocysts, which utilize built-in high osmotic pressures to inject a submicron tubule that penetrates and delivers their contents to the prey. Here we show, for the first time, that the nematocysts of the starlet sea anemone Nematostella vectensis can be isolated and incorporated into a topical formulation for continuous drug delivery. We demonstrate quantitative delivery of nicotinamide and lidocaine hydrochloride as a function of microcapsular dose or drug exposure. We also show how the released submicron tubules can be exploited as a skin penetration enhancer prior to and independently of drug application. The microcapsules are non-irritant and may offer an attractive alternative for hydrophilic transdermal drug delivery. Full article

(This article belongs to the Special Issue Mechanism of Action Analysis for Marine Compounds)

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Review

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1934 KiB

Open AccessReview

Targeting Nuclear Receptors with Marine Natural Products

by Chunyan Yang, Qianrong Li and Yong Li

Mar. Drugs 2014, 12(2), 601-635; https://doi.org/10.3390/md12020601 - 27 Jan 2014

Cited by 21 | Viewed by 12182

Abstract

Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators. Full article

(This article belongs to the Special Issue Mechanism of Action Analysis for Marine Compounds)

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