About: Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer

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About: Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer
Creator	Asimakopoulou, Antonia Chao, Celia Druzhyna, Nadiya Gerö, Domokos López-García, Isabel Mikros, Emmanuel Myrianthopoulos, Vassilios Módis, Katalin Olah, Gabor Papapetropoulos, Andreas Pavlidou, Athanasia Szabo, Csaba Szczesny, Bartosz Szoleczky, Petra Törö, Gabor Yanagi, Kazunori Hellmich, Mark Zatarain, John
Source	Elsevier; Medline; PMC
abstract	Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the `Killer Plates' collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H(2)S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H(2)S production) and were assessed for their ability to quench the H(2)S signal produced by the H(2)S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H(2)S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC(50): ~60 μM), tannic acid (IC(50): ~40 μM) and benserazide (IC(50): ~30 μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC(50): ~3 μM) and NSC67078 (IC(50): ~1 μM), while aurintricarboxylic acid (IC(50): ~3 μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC(50): ~1 μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC(50) of ~6 μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC(50): ~6 μM), tannic acid (IC(50): ~20 μM), benserazide (IC(50): ~20 μM), and NSC67078 (IC(50): ~0.3 μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC(50): ~300 μM). In contrast, although a CBS inhibitor in the cell-free assay, aurintricarboxylic acid failed to inhibit HCT116 proliferation at lower concentrations, and stimulated cell proliferation at 300 μM. Copper-containing compounds present in the libraries, were also found to be potent inhibitors of recombinant CBS; however this activity was due to the CBS inhibitory effect of copper ions themselves. However, copper ions, up to 300 μM, did not inhibit HCT116 cell proliferation. Benserazide was only a weak inhibitor of the activity of the other H(2)S-generating enzymes CSE and 3-MST activity (16% and 35% inhibition at 100 μM, respectively) in vitro. Benserazide suppressed HCT116 mitochondrial function and inhibited proliferation of the high CBS-expressing colon cancer cell line HT29, but not the low CBS-expressing line, LoVo. The major benserazide metabolite 2,3,4-trihydroxybenzylhydrazine also inhibited CBS activity and suppressed HCT116 cell proliferation in vitro. In an in vivo study of nude mice bearing human colon cancer cell xenografts, benserazide (50 mg/kg/day s.q.) prevented tumor growth. In silico docking simulations showed that benserazide binds in the active site of the enzyme and reacts with the PLP cofactor by forming reversible but kinetically stable Schiff base-like adducts with the formyl moiety of pyridoxal. We conclude that benserazide inhibits CBS activity and suppresses colon cancer cell proliferation and bioenergetics in vitro, and tumor growth in vivo. Further pharmacokinetic, pharmacodynamic and preclinical animal studies are necessary to evaluate the potential of repurposing benserazide for the treatment of colorectal cancers.
has issue date	2016-11-01(xsd:dateTime)
bibo:doi	10.1016/j.phrs.2016.08.016
bibo:pmid	27521834
has license	green-oa
sha1sum (hex)	84e44effbdcb3af03c815957ba63ea357327eeb3
schema:url	https://doi.org/10.1016/j.phrs.2016.08.016
resource representing a document's title	Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer
has PubMed Central identifier	PMC5107130
has PubMed identifier	27521834
schema:publication	Pharmacological Research
resource representing a document's body	covid:84e44effbdcb3af03c815957ba63ea357327eeb3#body_text
is schema:about of	named entity 'USED' named entity 'EXPERIMENTAL THERAPY' named entity '90%' named entity 'DRUG' named entity 'LIBRARY' named entity 'SUITABLE' named entity 'PHARMACOLOGICAL' named entity 'BENSERAZIDE' named entity 'SYNTHASE' named entity 'CYSTATHIONINE' named entity 'INHIBITION' named entity 'SCREENING' named entity 'CHARACTERIZED' named entity 'COMPOSITE' named entity 'DRUGS' named entity 'OF COLON CANCER' named entity 'metabolism' named entity 'CBS' named entity 'Benserazide' named entity 'substrate' named entity 'CBS' named entity 'fluorescence' named entity 'benserazide' named entity 'HCT116' named entity 'atom' named entity 'CBS' named entity 'catenin' named entity 'lactic acid' named entity 'CBS' named entity 'catenin' named entity 'CBS' named entity 'salts' named entity 'screening assay' named entity 'bladder' named entity 'PLP' named entity 'lyase' named entity 'aurintricarboxylic acid' named entity 'plasma levels' named entity 'fluorescent' named entity 'thymidylate synthase' named entity 'electrophilic' named entity 'rutin' named entity 'Piscataway' named entity 'sulfide' named entity 'enzyme responsible' named entity 'CBS' named entity 'plasma' named entity 'benserazide' named entity 'tumor' named entity 'potency' named entity 'non-specific' named entity 'fluorescence' named entity 'glycinamide ribonucleotide formyltransferase' named entity 'CBS' named entity 'cystathionine' named entity 'sulfide' named entity 'xenografts' named entity 'absorbance' named entity 'PLP' named entity 'dihydrofolate reductase' named entity 'hyperhomocysteinemia' named entity 'PLP' named entity 'pH 8' named entity 'CBS'

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