Ascidian Toxins with Potential for Drug Development

Watters, Dianne Josephine

doi:10.3390/md16050162

Cited by 53 publications

(34 citation statements)

References 193 publications

(242 reference statements)

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“…Notably, in the MCF-7 cell line, which was sensitized to irinotecan by GA-13315, the changes in mRNA expression levels were uncoupled with that of the protein expression levels for Top1, Chk1 and Bax. This imbalance between gene and protein expression levels may be caused by the potential effects of GA-13315 on the mRNA (half-life) stability (41)(42)(43). This phenomenon was not observed in HCT116 cells, thus the sensitizing effect of GA-13315 was probably associated with the disruption of the protein translation process; however, this hypothesis requires further investigation.…”

Section: Discussionmentioning

confidence: 93%

Chronic exposure to the gibberellin derivative GA‑13315 sensitizes breast cancer MCF‑7 cells but not colon cancer HCT116 cells to irinotecan

et al. 2020

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13-Chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315) is a gibberellin derivative that exhibits selective cytotoxicity to multidrug resistant MCF-7/ADR cells and reverses drug resistance when administered at subtoxic doses in combination with chemotherapy drugs. The present study aimed to investigate the impact of chronic GA-13315 exposure on the chemosensitivity of MCF-7 and HCT116 cell lines. Cells were administered a subtoxic dose of 1 µM GA-13315 for 12 weeks and the sensitivity of the cells to GA-13315, irinotecan and cisplatin, was assessed. The Cell Counting Kit-8 assay results demonstrated that the chronic exposure did not induce resistance to GA-13315, in either MCF-7 or HCT116 cells. Notably, MCF-7 cells were sensitized to irinotecan following exposure to GA-13315; however, HCT116 cells were not. The sensitizing effect of GA-13315 was associated with the alterations of topoisomerase 1 (Top1) protein expression, tyrosyl DNA phosphodiesterase 1 and checkpoint kinase 1. Further analysis indicated that GA-13315 caused DNA fragmentation; however, DNA damage was not mediated by a Top1-dependent molecular mechanism, as GA-13315 was revealed not to be a Top1 poison, despite inhibiting the catalytic activity of Top1. Taken together, the results of the present study indicated that GA-13315 may be used for sensitizing MCF-7 cells to irinotecan, as the chronic exposure of GA-13315 to MCF-7 cells still showed sensitizing effects to irinotecan.

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Section: Discussionmentioning

confidence: 93%

Chronic exposure to the gibberellin derivative GA‑13315 sensitizes breast cancer MCF‑7 cells but not colon cancer HCT116 cells to irinotecan

et al. 2020

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“…Polyketide synthetases are large multienzyme machineries. Natural products having polyketide and non-ribosomal peptide (NRP) structures are generally found to be of microbial origin [13]. Polyketides and the synthetic analogs have been discovered as important lead compounds with various activities, such as blocking protein tyrosine phosphatase and inhibiting the ATP synthase complex [73].…”

Section: Polyketides From Ascidiansmentioning

confidence: 99%

Origins and Bioactivities of Natural Compounds Derived from Marine Ascidians and Their Symbionts

Dou

Dong

2019

Marine Drugs

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Marine ascidians are becoming important drug sources that provide abundant secondary metabolites with novel structures and high bioactivities. As one of the most chemically prolific marine animals, more than 1200 inspirational natural products, such as alkaloids, peptides, and polyketides, with intricate and novel chemical structures have been identified from ascidians. Some of them have been successfully developed as lead compounds or highly efficient drugs. Although numerous compounds that exist in ascidians have been structurally and functionally identified, their origins are not clear. Interestingly, growing evidence has shown that these natural products not only come from ascidians, but they also originate from symbiotic microbes. This review classifies the identified natural products from ascidians and the associated symbionts. Then, we discuss the diversity of ascidian symbiotic microbe communities, which synthesize diverse natural products that are beneficial for the hosts. Identification of the complex interactions between the symbiont and the host is a useful approach to discovering ways that direct the biosynthesis of novel bioactive compounds with pharmaceutical potentials.

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“…However, the genetic basis driving ascidians to contribute and adapt marine ecosystem remains to be elusive. It has been reported that metabolic products in ascidians, such as alkaloids, cyclic peptides, and polyketides, could demonstrate high defensive bioactivity that may facilitate host ecological success in environmental invasion and adaptation [8][9][10]. These bioactive compounds could be synthesized by ascidians or their bacterial symbionts [11,12].…”

Section: Introductionmentioning

confidence: 99%

Seasonal dynamics and starvation impact on the gut microbiome of urochordate ascidian Halocynthia roretzi

Wei

Gao²,

Yang

et al. 2020

anim microbiome

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Background: Gut microbiota plays important roles in host animal metabolism, homeostasis and environmental adaptation. However, the interplay between the gut microbiome and urochordate ascidian, the most closet relative of vertebrate, remains less explored. In this study, we characterized the gut microbial communities of urochordate ascidian (Halocynthia roretzi) across the changes of season and starvation stress using a comprehensive set of omic approaches including 16S rRNA gene amplicon sequencing, shotgun metagenomics, metabolomic profiling, and transcriptome sequencing. Results: The 16S rRNA gene amplicon profiling revealed that ascidians harbor indigenous gut microbiota distinctly different to the marine microbial community and significant variations in composition and abundance of gut bacteria, with predominant bacterial orders representing each season. Depressed alpha-diversities of gut microbiota were observed across starvation stress when compared to the communities in aquafarm condition. Synechococcales involving photosynthesis and its related biosynthesis was reduced in abundance while the enrichments of Xanthomonadales and Legionellales may facilitate bile acid biosynthesis during starvation. Metabolomics analysis found that long chain fatty acids, linolenic acid, cyanoamino acid, and pigments derived from gut bacteria were upregulated, suggesting a beneficial contribution of the gut microbiome to the ascidian under starvation stress. Conclusions: Our findings revealed seasonal variation of ascidian gut microbiota. Defense and energy-associated metabolites derived from gut microbiome may provide an adaptive interplay between gut microbiome and ascidian host that maintains a beneficial metabolic system across season and starvation stress. The diversity-generating metabolisms from both microbiota and host might lead to the co-evolution and environmental adaptation.

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Ascidian Toxins with Potential for Drug Development

Cited by 53 publications

References 193 publications

Chronic exposure to the gibberellin derivative GA‑13315 sensitizes breast cancer MCF‑7 cells but not colon cancer HCT116 cells to irinotecan

Chronic exposure to the gibberellin derivative GA‑13315 sensitizes breast cancer MCF‑7 cells but not colon cancer HCT116 cells to irinotecan

Origins and Bioactivities of Natural Compounds Derived from Marine Ascidians and Their Symbionts

Seasonal dynamics and starvation impact on the gut microbiome of urochordate ascidian Halocynthia roretzi

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