Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms
1
Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic
2
International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
3
Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 66263 Brno, Czech Republic
4
Griffith Institute for Drug Discovery, Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this paper as co-senior authors.
Cancers 2020, 12(12), 3781; https://doi.org/10.3390/cancers12123781
Received: 30 November 2020
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Accepted: 11 December 2020
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Published: 15 December 2020
(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)
Simple Summary
Combination of chemotherapeutics for the treatment of childhood cancer can lead to the use of lower cytotoxic drug doses and better therapeutic tolerability (i.e., lower side effects) for patients. We discovered novel molecular targets of two lead thiosemicarbazone agents of the di-2-pyridylketone thiosemicarbazone class. These molecular targets include: cyclooxygenase, the DNA repair protein, O6-methylguanine DNA methyltransferase, mismatch repair proteins, and topoisomerase 2α. This research also identifies promising synergistic interactions of these thiosemicarbazones particularly with the standard chemotherapeutic, celecoxib.
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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Keywords:
thiosemicarbazones; DpC; Dp44mT; celecoxib; temozolomide; etoposide; combined anti-cancer treatment; osteosarcoma; medulloblastoma; neuroblastoma
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MDPI and ACS Style
Paukovcekova, S.; Skoda, J.; Neradil, J.; Mikulenkova, E.; Chlapek, P.; Sterba, J.; Richardson, D.R.; Veselska, R. Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms. Cancers 2020, 12, 3781. https://doi.org/10.3390/cancers12123781
AMA Style
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):3781. https://doi.org/10.3390/cancers12123781
Chicago/Turabian StylePaukovcekova, Silvia, Jan Skoda, Jakub Neradil, Erika Mikulenkova, Petr Chlapek, Jaroslav Sterba, Des R. Richardson, and Renata Veselska. 2020. "Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms" Cancers 12, no. 12: 3781. https://doi.org/10.3390/cancers12123781
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