Targeting apoptosis pathways by natural compounds in cancer: marine compounds as lead structures and chemical tools for cancer therapy.
TL;DR: Natural compounds derived from marine organisms and their synthetic derivates are an important source for new therapeutics for single agent or combined therapy with other chemotherapeutics to support the struggle against cancer.
About: This article is published in Cancer Letters.The article was published on 2013-05-28. It has received 88 citations till now. The article focuses on the topics: Discodermolide.
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TL;DR: This review shows the compounds derived from marine sources that are currently in clinical trials against cancer and the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.
Abstract: The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.
226 citations
Cites background from "Targeting apoptosis pathways by nat..."
...It entered clinical trials against prostate cancer, malignant melanoma and non-small cell lung cancer, with a mechanism of action that involved oncosis (ischemic cell death) [86]....
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TL;DR: In this review, the progress on studies of antitumor peptides from marine sources is provided; the biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is presented.
Abstract: The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides.
124 citations
TL;DR: The isolated stellettin B (Stel B) from marine sponge Jaspis stellifera is isolated, and it is demonstrated that it induced G1 arrest, apoptosis and autophagy at low concentrations in human NSCLC A549 cells, indicating the antitumor potential of Stel B by targeting PI3K/Akt/mTOR pathway.
Abstract: Until now, there is not yet antitumor drug with dramatically improved efficacy on non-small cell lung cancer (NSCLC). Marine organisms are rich source of novel compounds with various activities. We isolated stellettin B (Stel B) from marine sponge Jaspis stellifera, and demonstrated that it induced G1 arrest, apoptosis and autophagy at low concentrations in human NSCLC A549 cells. G1 arrest by Stel B might be attributed to the reduction of cyclin D1 and enhancement of p27 expression. The apoptosis induction might be related to the cleavage of PARP and increase of ROS generation. Moreover, we demonstrated that Stel B induced autophagy in A549 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy markers of LC3B, p62 and Atg5. Meanwhile, Stel B inhibited the expression of PI3K-p110, and the phosphorylation of PDK1, Akt, mTOR, p70S6K as well as GSK-3β, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings indicate the antitumor potential of Stel B for NSCLC by targeting PI3K/Akt/mTOR pathway.
121 citations
120 citations
TL;DR: The lead compound in the lamellarins family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death.
Abstract: In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.
103 citations
Cites background from "Targeting apoptosis pathways by nat..."
...Indole and pyrrole alkaloids, such as topsentin [3,4], tambjamine D [5], spongiacidin C [6], the discorhabdines [7], bear therapeutic potential and are frequently considered as a source of anticancer drugs [8,9]....
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References
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TL;DR: This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003 and is able to identify only one de novo combinatorial compound approved as a drug in this 25 plus year time frame.
Abstract: This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision 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, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than “S” (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area ...
5,170 citations
"Targeting apoptosis pathways by nat..." refers background in this paper
...In fact, almost half of the drugs introduced between 1940 and 2006 were of natural origin or inspired by natural products clearly have a most dramatic impact in the area of cancer [1,2]....
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TL;DR: Recent technological advances that help to address issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening and unrealized expectations from current lead-generation strategies have led to a renewed interest in natural products in drug discovery.
Abstract: Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.
2,254 citations
"Targeting apoptosis pathways by nat..." refers background in this paper
...In fact, almost half of the drugs introduced between 1940 and 2006 were of natural origin or inspired by natural products clearly have a most dramatic impact in the area of cancer [1,2]....
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TL;DR: The history of drug discovery from marine natural products is reviewed, and by describing selected examples, the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials are examined.
Abstract: Drug discovery from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered in a tropical cone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Here, we review the history of drug discovery from marine natural products, and by describing selected examples, we examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials. Providing an outlook into the future, we also examine the advances that may further expand the promise of drugs from the sea.
1,002 citations
"Targeting apoptosis pathways by nat..." refers background in this paper
...As numerous comprehensive overviews on compounds from marine origin exist [3–6], we like to focus only on trials or are promising experimental drugs reported to affect apoptotic pathways in tumor cells....
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...Although discodermolide has shown more potent effects in tumor cells than paclitaxel and has also shown promising effects in murine models, the pharmaceutical company Novartis has withdrawn it from Phase I trials due to cytotoxicity problems [6]....
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TL;DR: It is argued that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of cospase activation.
Abstract: A current view is that cytotoxic stress, such as DNA damage, induces apoptosis by regulating the permeability of mitochondria. Mitochondria sequester several proteins that, if released, kill by activating caspases, the proteases that disassemble the cell. Cytokines activate caspases in a different way, by assembling receptor complexes that activate caspases directly; in this case, the subsequent mitochondrial permeabilization accelerates cell disassembly by amplifying caspase activity. We found that cytotoxic stress causes activation of caspase-2, and that this caspase is required for the permeabilization of mitochondria. Therefore, we argue that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of caspase activation.
748 citations
"Targeting apoptosis pathways by nat..." refers background in this paper
...An initiator as well as an effector role has been described for caspase-2 [22,37,38]....
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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
"Targeting apoptosis pathways by nat..." refers background in this paper
...As numerous comprehensive overviews on compounds from marine origin exist [3–6], we like to focus only on trials or are promising experimental drugs reported to affect apoptotic pathways in tumor cells....
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