Journal
ONCOTARGET
Volume 6, Issue 40, Pages 42411-42428Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6389
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
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Funding
- Grant Agency of Charles University (GAUK) [903113, SVV 260 183]
- Charles University [PRVOUK P37/5]
- European Social Fund
- state budget of the Czech Republic [CZ.1.07/2.3.00/30.0061]
- National Health and Medical Research Council (NHMRC) of Australia [1021607]
- NHMRC RD Wright Fellowship [1083057]
- National Health and Medical Research Council of Australia [1083057] Funding Source: NHMRC
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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 (T-1/2 = 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 anticancer 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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