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dc.contributor.authorSestak, Vit
dc.contributor.authorStariat, Jan
dc.contributor.authorCermanova, Jolana
dc.contributor.authorPotuckova, Eliska
dc.contributor.authorChladek, Jaroslav
dc.contributor.authorRoh, Jaroslav
dc.contributor.authorBures, Jan
dc.contributor.authorJansova, Hana
dc.contributor.authorPrusa, Petr
dc.contributor.authorSterba, Martin
dc.contributor.authorMicuda, Stanislav
dc.contributor.authorSimunek, Tomas
dc.contributor.authorKalinowski, Danuta S
dc.contributor.authorRichardson, Des R
dc.contributor.authorKovarikova, Petra
dc.date.accessioned2021-04-30T01:36:08Z
dc.date.available2021-04-30T01:36:08Z
dc.date.issued2015
dc.identifier.issn1949-2553en_US
dc.identifier.doi10.18632/oncotarget.6389en_US
dc.identifier.urihttp://hdl.handle.net/10072/404053
dc.description.abstractDi(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4--cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherImpact Journals, LLCen_US
dc.relation.ispartofpagefrom42411en_US
dc.relation.ispartofpageto42428en_US
dc.relation.ispartofissue40en_US
dc.relation.ispartofjournalOncotargeten_US
dc.relation.ispartofvolume6en_US
dc.subject.fieldofresearchOncology and Carcinogenesisen_US
dc.subject.fieldofresearchcode1112en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsCell Biologyen_US
dc.subject.keywordsDi(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazoneen_US
dc.titleNovel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agentsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationSestak, V; Stariat, J; Cermanova, J; Potuckova, E; Chladek, J; Roh, J; Bures, J; Jansova, H; Prusa, P; Sterba, M; Micuda, S; Simunek, T; Kalinowski, DS; Richardson, DR; Kovarikova, P, Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents, Oncotarget, 2015, 6 (40), pp. 42411-42428en_US
dcterms.dateAccepted2015-11-11
dcterms.licensehttp://creativecommons.org/licenses/by/3.0/en_US
dc.date.updated2021-04-30T01:34:03Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s) 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
gro.hasfulltextFull Text
gro.griffith.authorRichardson, Des R.


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