dc.contributor.author | Paukovcekova, Silvia | |
dc.contributor.author | Skoda, Jan | |
dc.contributor.author | Neradil, Jakub | |
dc.contributor.author | Mikulenkova, Erika | |
dc.contributor.author | Chlapek, Petr | |
dc.contributor.author | Sterba, Jaroslav | |
dc.contributor.author | Richardson, Des R | |
dc.contributor.author | Veselska, Renata | |
dc.date.accessioned | 2021-01-06T01:17:18Z | |
dc.date.available | 2021-01-06T01:17:18Z | |
dc.date.issued | 2020 | |
dc.identifier.issn | 2072-6694 | |
dc.identifier.doi | 10.3390/cancers12123781 | |
dc.identifier.uri | http://hdl.handle.net/10072/400667 | |
dc.description.abstract | Combining 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.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | MDPI AG | |
dc.relation.ispartofpagefrom | 3781 | |
dc.relation.ispartofissue | 12 | |
dc.relation.ispartofjournal | Cancers | |
dc.relation.ispartofvolume | 12 | |
dc.subject.fieldofresearch | Oncology and carcinogenesis | |
dc.subject.fieldofresearchcode | 3211 | |
dc.subject.keywords | Dp44mT | |
dc.subject.keywords | DpC | |
dc.subject.keywords | celecoxib | |
dc.subject.keywords | combined anti-cancer treatment | |
dc.subject.keywords | etoposide | |
dc.title | Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms. | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Paukovcekova, 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.dateAccepted | 2020-12-11 | |
dcterms.license | http://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2021-01-06T01:09:37Z | |
dc.description.version | Version 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.hasfulltext | Full Text | |
gro.griffith.author | Richardson, Des R. | |