Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis

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

doi:10.1016/j.bmc.2015.05.006

Cited by 19 publications

(17 citation statements)

References 31 publications

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“…Different biological targets have been identified, like DNA [37][38][39], RNA [40] and several enzymes as RNA-dependent DNA polymerases [41], xanthine oxidoreductase [42], thioredoxin reductase [43,44], topoisomerase IIa [45][46][47] or succinate and NADH dehydrogenases [48] and, mainly, the ribonucleotide reductases (RDRs, [49][50][51]), where TSC-Fe and TSC-Cu complexes seem to affect the tyrosyl radical in the active site [52] or to sequestrate the iron from the active centre [53]. The presence of redox-active metal ions also provokes the interaction with cell thiols and further formation of reactive oxygen species (ROS) triggers oxidative processes in different cell structures and organelles [54][55][56]. Thus, the reduced form of glutathione (GSH) reacts with TSC-Cu II and TSC-Fe III entities to give oxidized GSSG species and Cu I or Fe II ions [57], whose re-oxidation processes yield ROS [58,59].…”

Section: -Introductionmentioning

confidence: 99%

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

García–Tojal

Gil‐García

Fouz

et al. 2018

Journal of Inorganic Biochemistry

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Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-Cu complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO)] compound (1) (HPTSC=pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu(PTSC*)(ONO)}] derivative (2, HPTSC*=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of Cu ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands.

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Section: -Introductionmentioning

confidence: 99%

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

García–Tojal

Gil‐García

Fouz

et al. 2018

Journal of Inorganic Biochemistry

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“…Even high concentrations of the thiosemicarbazones ([20 lM) failed to result in [90 % cytotoxicity, whereas the corresponding Cu(II) complexes were significantly more potent with IC 90 of the those complexes around 1 lM (Akladios et al 2015). We did not observe a similar enhancement for the iron complexes of the thiosemicarbazone in that study.…”

Section: Introductionmentioning

confidence: 50%

“…Such differences in the cytotoxicity did not coincide with potency of different preformed complexes of Dp44mT on the leukemia line HL-60 (Bernhardt et al 2008). We previously demonstrated that the thiosemicarbazone (4b) showed a flattening of the dose response curve resulting in a fraction affected (Fa) value around 0.5 from a dose of 1 lM through to 25 lM against MCF-7 cells (Akladios et al 2015). This plateau in cytotoxicity was observed with all thiosemicarbazones in the class with the exception of the relatively inactive parent (Compound 4a, see Table 1) (Fig.…”

Section: Resultsmentioning

confidence: 89%

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

2015

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Zinc is the second most abundant transition metal in the human body, between 3 and 10% of human genes encoding for zinc binding proteins. We have investigated the interplay of reactive oxygen species and zinc homeostasis on the cytotoxicity of the thiosemicarbazone chelators against the MCF-7 cell line. The cytotoxicity of thiosemicarbazone chelators against MCF-7 can be improved through supplementation of ionic zinc provided the zinc ion is at a level exceeding the thiosemicarbazone concentration. Elimination of the entire cell population can be accomplished with this regime, unlike the plateau of cytotoxicity observed on thiosemicarbazone monotherapy. The cytotoxic effects of copper complexes of the thiosemicarbazone are not enhanced by zinc supplementation, displacement of copper from the complex being disfavoured. Treatment of MCF-7 with uncomplexed thiosemicarbazone initiates post G1 blockade alongside the induction of apoptosis, cell death being abrogated through subsequent supplementation with zinc ion after drug removal. This would implicate a metal depletion mechanism in the cytotoxic effect of the un-coordinated thiosemicarbazone. The metal complexes of the species, however, fail to initiate similar G1 blockade and apparently exert their cytotoxic effect through generation of reactive oxygen species, suggesting that multiple mechanisms of cytotoxicity can be associated with the thiosemicarbazones dependant on the level of metal ion association.

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“…2,3 Cancer cells operate under a high level of oxidative stress, due to high baseline levels of reactive oxygen species, oncogenic transformation, and metabolic reprogramming. 4 Oxidative stress occurs due to imbalance between the production of free radicals [superoxide anion (O 2 -), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (OH -), nitric oxide (NO), and more] and their elimination by antioxidant defense mechanisms [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), among others], which induces cell damage caused by lipid peroxidation generating derangement and loss of function and integrity of the cell membrane, as well as DNA damage, promoting genomic instability and cell proliferation, thereby increasing the somatic mutations and neoplastic transformation. 5,6 According to the Brazilian National Cancer Institute (INCA, in the Portuguese acronym), in 2012 there were 14.1 million cases of cancer in the world, with a total of 8.2 million deaths from the disease.…”

Section: Introductionmentioning

confidence: 99%

Ascorbic acid in the prevention and treatment of cancer

Mata

Carvalho

Alencar

et al. 2016

Rev. Assoc. Med. Bras.

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Mata aMOF da et al. 680rev assoC med bras 2016; 62(7):680-686 This review is aimed at the systematic mapping of ascorbic acid in the prevention and/or treatment of cancer in clinical and non-clinical studies from 2011 to 2015, in order to understand dose-response variations as well as its mechanisms of action as an antioxidant and antitumor agent. Seventy-eight articles were retrieved from the PubMed/Bireme database, of which only 30 included ascorbic acid in the prevention and/or treatment of cancer. However, there are controversies regarding doses and a lack of clinical studies featuring its mechanism of action more clearly. Other studies are needed to understand dose-response variations, as well as its targeting mechanisms of action, both as an antioxidant and antitumor agent, to assist treatment and prevention of cancer, aiming at better quality of life for both patients and the general population.

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Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis

Cited by 19 publications

References 31 publications

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

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

Ascorbic acid in the prevention and treatment of cancer

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