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Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms

S. Paukovcekova, J. Skoda, J. Neradil, E. Mikulenkova, P. Chlapek, J. Sterba, DR. Richardson, R. Veselska,

. 2020 ; 12 (12) : . [pub] 20201215

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc21001536

Grant support
17-33104A Ministerstvo Zdravotnictví Ceské Republiky

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.

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$a 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.
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$a Neradil, Jakub $u Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic. International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
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$a Mikulenkova, Erika $u Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic. International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
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$a Chlapek, Petr $u Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic. International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
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$a Sterba, Jaroslav $u International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic. Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 66263 Brno, Czech Republic.
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$a Richardson, Des R $u Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic. Griffith Institute for Drug Discovery, Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia.
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$a Veselska, Renata $u Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic. International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic. Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 66263 Brno, Czech Republic.
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