Show simple item record

dc.contributor.authorPaukovcekova, Silvia
dc.contributor.authorSkoda, Jan
dc.contributor.authorNeradil, Jakub
dc.contributor.authorMikulenkova, Erika
dc.contributor.authorChlapek, Petr
dc.contributor.authorSterba, Jaroslav
dc.contributor.authorRichardson, Des R
dc.contributor.authorVeselska, Renata
dc.date.accessioned2021-01-06T01:17:18Z
dc.date.available2021-01-06T01:17:18Z
dc.date.issued2020
dc.identifier.issn2072-6694
dc.identifier.doi10.3390/cancers12123781
dc.identifier.urihttp://hdl.handle.net/10072/400667
dc.description.abstractCombining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherMDPI AG
dc.relation.ispartofpagefrom3781
dc.relation.ispartofissue12
dc.relation.ispartofjournalCancers
dc.relation.ispartofvolume12
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchcode3211
dc.subject.keywordsDp44mT
dc.subject.keywordsDpC
dc.subject.keywordscelecoxib
dc.subject.keywordscombined anti-cancer treatment
dc.subject.keywordsetoposide
dc.titleNovel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms.
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationPaukovcekova, S; Skoda, J; Neradil, J; Mikulenkova, E; Chlapek, P; Sterba, J; Richardson, DR; Veselska, R, Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms., Cancers, 2020, 12 (12), pp. 3781
dcterms.dateAccepted2020-12-11
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-01-06T01:09:37Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorRichardson, Des R.


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record