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

J 2020

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

PAUKOVČEKOVÁ, Silvia, Jan ŠKODA, Jakub NERADIL, Erika MIKULENKOVÁ, Petr CHLAPEK et. al.

Basic information

Original name

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

Authors

PAUKOVČEKOVÁ, Silvia (703 Slovakia, belonging to the institution), Jan ŠKODA (203 Czech Republic, belonging to the institution), Jakub NERADIL (203 Czech Republic, belonging to the institution), Erika MIKULENKOVÁ (203 Czech Republic, belonging to the institution), Petr CHLAPEK (203 Czech Republic, belonging to the institution), Jaroslav ŠTĚRBA (203 Czech Republic, belonging to the institution), Desi Raymond RICHARDSON (36 Australia, belonging to the institution) and Renata VESELSKÁ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Cancers, Basel, MDPI, 2020, 2072-6694

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10603 Genetics and heredity

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.639

RIV identification code

RIV/00216224:14310/20:00117866

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.3390/cancers12123781

UT WoS

000602249000001

Keywords in English

thiosemicarbazones; DpC; Dp44mT; celecoxib; temozolomide; etoposide; combined anti-cancer treatment; osteosarcoma; medulloblastoma; neuroblastoma

Abstract

V originále

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 2 alpha. 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, O-6-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 2 alpha (Topo2 alpha), 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.

Links

MUNI/A/1409/2019, interní kód MU

Name: Personalizovaná léčba v dětské onkologii: na cestě k "liquid dynamic medicine" a "N-of-1 clinical trials"

Investor: Masaryk University, Category A

NV17-33104A, research and development project

Name: Terapeutický potenciál nových thiosemicarbazonů v dětské onkologii: možnosti překonání Pgp-zprostředkované lékové rezistence

Citovat

PAUKOVČEKOVÁ, Silvia, Jan ŠKODA, Jakub NERADIL, Erika MIKULENKOVÁ, Petr CHLAPEK, Jaroslav ŠTĚRBA, Desi Raymond RICHARDSON and Renata VESELSKÁ. Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms. Cancers. Basel: MDPI, 2020, vol. 12, No 12, p. 1-23. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers12123781.

@article{1730145,
   author = {Paukovčeková, Silvia and Škoda, Jan and Neradil, Jakub and Mikulenková, Erika and Chlapek, Petr and Štěrba, Jaroslav and Richardson, Desi Raymond and Veselská, Renata},
   article_location = {Basel},
   article_number = {12},
   doi = {http://dx.doi.org/10.3390/cancers12123781},
   keywords = {thiosemicarbazones; DpC; Dp44mT; celecoxib; temozolomide; etoposide; combined anti-cancer treatment; osteosarcoma; medulloblastoma; neuroblastoma},
   language = {eng},
   issn = {2072-6694},
   journal = {Cancers},
   title = {Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms},
   url = {https://doi.org/10.3390/cancers12123781},
   volume = {12},
   year = {2020}
}

TY  - JOUR
ID  - 1730145
AU  - Paukovčeková, Silvia - Škoda, Jan - Neradil, Jakub - Mikulenková, Erika - Chlapek, Petr - Štěrba, Jaroslav - Richardson, Desi Raymond - Veselská, Renata
PY  - 2020
TI  - Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms
JF  - Cancers
VL  - 12
IS  - 12
SP  - 1-23
EP  - 1-23
PB  - MDPI
SN  - 20726694
KW  - thiosemicarbazones
KW  - DpC
KW  - Dp44mT
KW  - celecoxib
KW  - temozolomide
KW  - etoposide
KW  - combined anti-cancer treatment
KW  - osteosarcoma
KW  - medulloblastoma
KW  - neuroblastoma
UR  - https://doi.org/10.3390/cancers12123781
L2  - https://doi.org/10.3390/cancers12123781
N2  - 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 2 alpha. 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, O-6-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 2 alpha (Topo2 alpha), 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.
ER  -

PAUKOVČEKOVÁ, Silvia, Jan ŠKODA, Jakub NERADIL, Erika MIKULENKOVÁ, Petr CHLAPEK, Jaroslav ŠTĚRBA, Desi Raymond RICHARDSON and Renata VESELSKÁ. Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms. \textit{Cancers}. Basel: MDPI, 2020, vol.~12, No~12, p.~1-23. ISSN~2072-6694. Available from: https://dx.doi.org/10.3390/cancers12123781.

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