Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores

Akladios, Fady N.; Andrew, Scott D.; Parkinson, C. J.

doi:10.1007/s10534-015-9905-1

Cited by 7 publications

(1 citation statement)

References 21 publications

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“…On the other hand, it has been reported that Dp44mT and their complexes with iron and copper cause apoptosis by generating cytotoxic ROS [ 23 , 40 ]. Moreover, Akladios et al reported that in some TSC, the addition of metal cations may increase activity [ 41 , 42 ]. This observation led to the alternative use of TSC as ionophores.…”

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confidence: 99%

The role of oxidative stress in activity of anticancer thiosemicarbazones

et al. 2018

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Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium.

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Section: Introductionmentioning

confidence: 99%

The role of oxidative stress in activity of anticancer thiosemicarbazones

et al. 2018

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Cytotoxic activity of expanded coordination bis-thiosemicarbazones and copper complexes thereof

2016

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A series of bis-thiosemicarbazone agents with coordinating groups capable of multiple metal coordination modes has been generated and evaluated for potential cytotoxic effects against melanoma (MelRm) and breast adenocarcinoma (MCF-7) cell lines. The bis-thiosemicarbazones in this study generally demonstrated superior cytotoxic activity against MelRm than MCF-7 in the absence of metal ion supplementation, but in most cases could not be considered superior to the reference thiosemicarbazone Dp44mT. The key structural features for the cytotoxic activity were the central metal binding atom on the aromatic core, the thiocarbonyl residue and the nature of substitution on the N4-terminus in terms of size and lipophilicity. The cytotoxicity of bis-thiosemicarbazone ligands improved significantly with Cu(II) supplementation, particularly against MCF-7 cells. The mechanism of cytotoxicity of bis-thiosemicarbazones was proposed to be dependent on the combined effect of metal mobilisation and ROS generation which is so called a "double-punch effect".

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Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents

2016

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The cytotoxic activity of thiosemicarbazones (TSC) and thiocarbohydrazones was investigated against the MelRm melanoma cell line. In general, the melanoma line was susceptible to metal coordinating agents, the most useful of which incorporated the dipyridyl ketone hydrazone sub-structure. The impact of copper supplementation on the cytotoxic activity towards the melanoma line (MelRm) of metal coordinating agents when acting as ionophores is less predictable than the general improvement that has been seen in other cancer cells such as breast adenocarcinoma (MCF-7). The bimetallic nature of thiocarbohydrazone complexes with resultant loss of lipophilicity is a limiting factor in usage against MelRm. The cytotoxic activity of TSC against MelRm when used as copper ionophores could be markedly improved through combination with a partner drug capable of disrupting cellular defences to oxidative stress. In the absence of copper supplementation, both TSC and thiocarbohydrazones could be used to initiate cell cycle arrest and this could be employed to improve cytotoxicity profiles of other metallodrugs such as cisplatin.

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Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores

Cited by 7 publications

References 21 publications

The role of oxidative stress in activity of anticancer thiosemicarbazones

The role of oxidative stress in activity of anticancer thiosemicarbazones

Cytotoxic activity of expanded coordination bis-thiosemicarbazones and copper complexes thereof

Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents

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