Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 II. Physico-chemical Properties and Structure Elucidation

Sakai, Takashi; Asai, Naoki; Okuda, Akifumi; Kawamura, Naoto; Mizui, Yoshiharu

doi:10.7164/antibiotics.57.180

Cited by 84 publications

(56 citation statements)

References 7 publications

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“…We performed a high throughput screening and as a result identified a series of microbial products that inhibit hypoxia-induced PLAP expression5). They are structurally novel 12-membered macrolides, which we designate as pladienolides5, 6) In this report, we describe the in vitro and in vivo antitumor activities of pladienolides. These substances show highly potent antitumor activity both in vitro and in vivo, and may thus have potential for use in anticancer therapy.…”

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confidence: 99%

Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 III. In Vitro and In Vivo Antitumor Activities

et al. 2004

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We have discovered seven novel 12-membered macrolides, pladienolides A to G, from Streptomyces platensis Mer-11107, with pladienolide B the most potently inhibiting hypoxia induced-VEGF expression and proliferation of the U251 cancer cell line. A growth inhibitory study using a 39-cell line drug-screening panel demonstrated that pladienolide B has strong antitumor activities in vitro. A COMPARE analysis reveals that it has a unique antitumor spectrum that sets it apart from anticancer drugs currently in clinical use. This result suggests that pladienolide B has a novel mechanism of action. A series of xenograft studies were conducted to evaluate the in vivo potency of pladienolides. Pladienolide B extensively inhibited tumor growth in xenograft models. In the most sensitive model, using BSY-1 xenografts, tumors were completely regressed by administration of pladienolide B. For the reason of their novel mechanism of action and excellent in vivo efficacy, pladienolides appear to have major potential for use in cancer treatment.Tumor cells are frequently exposed to severe hypoxia. To survive and grow under hypoxic conditions, tumors adapt to their environment by activating a series of cascading events.This opens the possibility of creating novel antitumor drugs that interfere with the signaling involved in these adaptation processes. One key regulator for hypoxia adaptation is known to be hypoxia-inducible factor-1 (HIF-1)1). HIF-1 is an essential transcription factor and is composed of two basic helix-loop-helix (HLH) PAS transcription subunits, as targets for antitumor drug development2,3). However, it is difficult for small molecules to inhibit HIF-1 directly, since it is an HLH transcription factor. Accordingly, several groups are searching for compounds that inhibit the HIF-1 pathway, using a reporter gene assay controlled by hypoxiaresponsive element (HRE), an HIF-1 binding sequence4).We also have developed a cell-base screening system using VEGF promoter (2.3kb) containing endogenous HRE to search for HIF pathway modulators. The system is based on genetically engineered U251 human glioma cells that stably express a recombinant vector in which the placental alkaline phosphatase (PLAP) reporter gene is placed under the control of the human VEGF promoter. We performed a high throughput screening and as a result identified a series of microbial products that inhibit hypoxia-induced PLAP expression5). They are structurally novel 12-membered macrolides, which we designate as pladienolides5,6)In this report, we describe the in vitro and in vivo antitumor activities of pladienolides. These substances show highly potent antitumor activity both in vitro and in vivo, and may thus have potential for use in anticancer therapy.

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Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 III. In Vitro and In Vivo Antitumor Activities

et al. 2004

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“…Among experimentally characterized biosynthetic genes, the new sequence from CNH-643 (new KS1) shares closest amino acid identity (60%) to a KS domain associated with epothilone biosynthesis in Sorangium cellulosum (14). The new sequence from CNH-905 (new KS2) shares 73% amino acid identity to a KS domain associated with the biosynthesis of the polyketide-derived secondary metabolite pladienolide (22).…”

Section: Resultsmentioning

confidence: 98%

Geographic Distribution of Secondary Metabolite Genes in the Marine Actinomycete Salinispora arenicola

Edlund

Loesgen

Fenical

et al. 2011

Appl Environ Microbiol

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The molecular fingerprinting technique terminal-restriction fragment length polymorphism (T-RFLP) was used in combination with sequence-based approaches to evaluate the geographic distribution of secondary metabolite biosynthetic genes in strains of the marine actinomycete Salinispora arenicola. This study targeted ketosynthase (KS) domains from type I polyketide synthase (PKS) genes and revealed four distinct clusters, the largest of which was comprised of strains from all six global locations sampled. The remaining strains fell into three smaller clusters comprised of strains derived entirely from the Red Sea, the Sea of Cortez, or around the Island of Guam. These results reveal variation in the secondary metabolite gene collectives maintained by strains that are largely clonal at the 16S rRNA level. The location specificities of the three smaller clusters provide evidence that collections of secondary metabolite genes in subpopulations of S. arenicola are endemic to these locations. Cloned KS sequences support the maintenance of distinct sets of biosynthetic genes in the strains associated with each cluster and include four that had not previously been detected in S. arenicola. Two of these new sequences were observed only in strains derived from Guam or the Sea of Cortez. Transcriptional analysis of one of the new KS sequences in conjunction with the production of the polyketide arenicolide A supports a link between this sequence and the associated biosynthetic pathway. From the perspective of natural product discovery, these results suggest that screening populations from distant locations can enhance the discovery of new natural products and provides further support for the use of molecular fingerprinting techniques, such as T-RFLP, to rapidly identify strains that possess distinct sets of biosynthetic genes.The genus Salinispora is an obligate marine actinomycete taxon comprised of the formally described species S. tropica and S. arenicola (17) and a third species for which the name "S. pacifica" has been proposed (12). The genus is broadly distributed in tropical and subtropical marine sediments, with S. arenicola displaying the widest geographical range (12). While the genus is clearly resolved based on 16S rRNA phylogeny, the three species share 99% 16S sequence identity and are better resolved using less-conserved phylogenetic markers (12). To date, no intraspecific diversity has been reported for S. tropica, and only a few nucleotide changes have been observed in S. arenicola, including two polymorphisms that are restricted to populations from the Sea of Cortez (12).Bacteria that share closely related or identical 16S rRNA gene sequences can vary greatly at the genomic level (27). These genomic differences often are concentrated in islands, regions of the chromosome that are known to house genes associated with ecological adaptation (3). A comparative analysis of the genome sequences of S. tropica (strain CNB-440) and S. arenicola (strain CNS-205) revealed 21 major genomic islands, within which secon...

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“…Dozens of small molecule effectors targeting the alternative splicing process have been identified and evaluated as drug candidates, including a natural product of Pseudomonas sp. number 2663 called FR901464 [9], natural products from Streptomyces platensis Mer-11107 that originated the group of Pladienolides [37], Herboxidiene [15], and Isoginkgetin [38]. These molecules and their derivatives have shown activity as splicing inhibitors and many of them demonstrated potent antiproliferative properties in human cancer cell lines, being in general less toxic to normal human cells [39].…”

Section: Microbial Metabolites That Regulate Splicingmentioning

confidence: 99%

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

Martínez-Montiel

Rosas-Murrieta

Martínez-Montiel

et al. 2016

BioMed Research International

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In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.

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Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 II. Physico-chemical Properties and Structure Elucidation

Cited by 84 publications

References 7 publications

Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 III. In Vitro and In Vivo Antitumor Activities

Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107 III. In Vitro and In Vivo Antitumor Activities

Geographic Distribution of Secondary Metabolite Genes in the Marine Actinomycete Salinispora arenicola

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

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