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Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents

Vit Sestak, Jan Stariat, Jolana Cermanova, Eliska Potuckova, Jaroslav Chladek, Jaroslav Roh, Jan Bures, Hana Jansova, Petr Prusa, Martin Sterba, Stanislav Micuda, Tomas Simunek, Danuta S. Kalinowski, Des R. Richardson and Petra Kovarikova _

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Oncotarget. 2015; 6:42411-42428. https://doi.org/10.18632/oncotarget.6389

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Abstract

Vit Sestak1, Jan Stariat1, Jolana Cermanova2, Eliska Potuckova3, Jaroslav Chladek2, Jaroslav Roh4, Jan Bures1, Hana Jansova3, Petr Prusa4, Martin Sterba2, Stanislav Micuda2, Tomas Simunek3, Danuta S. Kalinowski5, Des R. Richardson5 and Petra Kovarikova1

1 Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic

2 Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova, Hradec Kralove, Czech Republic

3 Department of Biochemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic

4 Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic

5 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia

Correspondence to:

Des R. Richardson, email:

Petra Kovarikova, email:

Keywords: Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone, di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, anti-cancer agents, metabolism, pharmacokinetics

Received: September 17, 2015 Accepted: November 11, 2015 Published: November 25, 2015

Abstract

Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.


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