Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

Salvador, Lilibeth A.; Luesch, Hendrik

doi:10.2174/138945012802008973

Cited by 26 publications

(20 citation statements)

References 128 publications

(222 reference statements)

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“…HDACi of various chemical shapes and sizes are secreted by a wide range of organisms, often to kill, or at least suppress the growth of, competing life forms, (reviewed by Salvador and Luesch ). Some examples are presented in Table .…”

Section: Hdaci Are Natural Products That Can Kill or Manipulate Compementioning

confidence: 99%

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Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Halsall

Turner

2016

BioEssays

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Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers.Also see the video abstract here.

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Section: Hdaci Are Natural Products That Can Kill or Manipulate Compementioning

confidence: 99%

“…The table shows the basic chemical structures of naturally occurring HDACi, organisms that make them and, where known, the organisms against which they act in vivo. Detailed chemical structures for the inhibitors listed can be found in the review by Salvador and Luesch .…”

Section: Hdaci Are Natural Products That Can Kill or Manipulate Compementioning

confidence: 99%

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Halsall

Turner

2016

BioEssays

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“…10 Most of these naturally occurring HDAC inhibitors are proposed to directly chelate the active site Zn 2+ ions of the enzymes with the exception of the epoxides, which are reported to form covalent bonds with the HDACs. 10 …”

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confidence: 99%

A Potent HDAC Inhibitor, 1-Alaninechlamydocin, from a Tolypocladium sp. Induces G2/M Cell Cycle Arrest and Apoptosis in MIA PaCa-2 Cells

Risinger

King

et al. 2014

J. Nat. Prod.

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The cyclic tetrapeptide 1-alaninechlamydocin was purified from a Great Lakes-derived fungal isolate identified as a Tolypocladium sp. Although the planar structure was previously described, a detailed analysis of its spectroscopic data and biological activity are reported here for the first time. Its absolute configuration was determined using a combination of spectroscopic (1H–1H ROESY, ECD, and X-ray diffraction) and chemical (Marfey’s analysis) methods. 1-Alaninechlamydocin showed potent antiproliferative/cytotoxic activities in a human pancreatic cancer cell line (MIA PaCa-2) at low-nanomolar concentrations (GI50 5.3 nM, TGI 8.8 nM, LC50 22 nM). Further analysis revealed that 1-alaninechlamydocin induced G2/M cell cycle arrest and apoptosis. Similar to other cyclic epoxytetrapeptides, the inhibitory effects of 1-alaninechlamydocin are proposed to be produced primarily via inhibition of histone deacetylase (HDAC) activity.

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“…103,104 Largazole thiol features a 3-hydroxy-7-mercaptohept-4-enoic acid moiety, a characteristic structural feature of the cyclic depsipeptides FK228, FR-901375, 105 and spiruchostatins. 106,107 This moiety is also disguised in FK228, FR-901375 and spiruchostatins as a disulfide, which requires glutathione-assisted reduction to liberate the bioactive species. 95 FK228 was first shown to inhibit HDACs by similarity of its phenotypic effect with the known HDAC inhibitor trichostatin A in a screen for activators of SV40 promoter-dependent transcription.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

Biological targets and mechanisms of action of natural products from marine cyanobacteria

2015

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Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial.

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Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

Cited by 26 publications

References 128 publications

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

A Potent HDAC Inhibitor, 1-Alaninechlamydocin, from a Tolypocladium sp. Induces G2/M Cell Cycle Arrest and Apoptosis in MIA PaCa-2 Cells

Biological targets and mechanisms of action of natural products from marine cyanobacteria

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