Copper binding promotes the interaction of cisplatin with human copper chaperone Atox1

Zhang, Xi; Guo, Wei; Tian, Changlin; Wang, Fuyi; Liu, Yangzhong

doi:10.1039/c3cc45905e

Cited by 40 publications

(55 citation statements)

References 27 publications

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“…Much is however not known about the levels or the role of copper in hepatocellular carcinoma. Our study is possibly the first to show that the increase in copper levels is almost ten fold, as compared to a usual elevation of two to five folds in other malignancies [6]. While our laboratory is actively engaged in determining the possible causes and functions of such a significant elevation in copper, it has not escaped our notice that this metabolic feature can be utilized for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 88%

“…Since elevation in copper levels can be as high as two to five folds in malignancies [5], this metabolic difference is being actively targeted to develop strategies to combat the disease. It has been previously shown that standard chemotherapeutic drugs, such as cisplatin [6], methotrexate [7], 5-flourouracil [8] and cyclophosphamide [9] and naturally occurring chemotherapeutic compounds, such as plant derived polyphenolic compounds [10,11] also interact with cellular copper, and this interact may in part, be responsible for their chemotherapeutic effects.…”

Section: Introductionmentioning

confidence: 98%

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Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

et al. 2016

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Calcitriol is the metabolically active form of Vitamin D and is known to kill cancer cells. Using the rat model of DEN induced hepatocellular carcinoma we show that there is a marked increase in cellular levels of copper in hepatocellular carcinoma and that calcitriol-copper interaction leads to reactive oxygen species mediated DNA breakage selectively in hepatocellular carcinoma cells. In vivo studies show that calcitriol selectively induces severe fluctuations in cellular enzymatic and non enzymatic scavengers of reactive oxygen species in the malignant tissue. Lipid peroxidation, a well established marker of oxidative stress, was found to increase, and substantial cellular DNA breakage was observed. We propose that calcitriol is a proxidant in the cellular milieu of hepatocellular carcinoma cells, and this copper mediated prooxidant action of calcitriol causes selective DNA breakage in malignant cells, while sparing normal (non malignant) cells.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 98%

Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

et al. 2016

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“…The presence of TCEP during incubation of Atox1 with cisplatin induced the formation of the adduct [Atox1+Pt(TCEP) 2 ] 2+ , indicating the coordination of two phosphorus atoms from TCEP on platinum, in addition to two cysteine residues from the protein. [192] The influence of copper binding on Atox1 with respect to the reactivity of cisplatin has been further investigated by Liu et al using 2D NMR spectroscopy and ESI-MS. [193] Copper coordination to Atox1 promoted significantly the binding of platinum to the protein and prevented metal release upon incubation with reducing agents such as DTT. [193] The nature of the platination sites on both apo-and holo-Atox1 was investigated using a bottom-up approach.…”

Section: Copper Transporters and Chaperonsmentioning

confidence: 99%

“…[192] The influence of copper binding on Atox1 with respect to the reactivity of cisplatin has been further investigated by Liu et al using 2D NMR spectroscopy and ESI-MS. [193] Copper coordination to Atox1 promoted significantly the binding of platinum to the protein and prevented metal release upon incubation with reducing agents such as DTT. [193] The nature of the platination sites on both apo-and holo-Atox1 was investigated using a bottom-up approach. After tryptic digestion, the obtained fragments were then analysed using CID and the residues Cys12 and Cys15 were confirmed as the platination sites in both cases, as observed by X-ray crystallography.…”

Section: Copper Transporters and Chaperonsmentioning

confidence: 99%

“…After tryptic digestion, the obtained fragments were then analysed using CID and the residues Cys12 and Cys15 were confirmed as the platination sites in both cases, as observed by X-ray crystallography. [190,193] Interestingly, to evaluate the reactivity of Pt(IV) prodrugs interactions towards copper transporters, two model peptides (the octapeptide Mets7 (Met-Thr-Gly-Met-Lys-Gly-Met-Ser), resembling to one of the Met-rich motifs present on the extracellular N-terminal domain of hCtr1, and MNK1, the first cytoplasmic domain of ATP7A) have been incubated and analysed by ESI-MS by Osella et al [194] Both apo-peptides were found to be unreactive towards the dicarboxylato Pt(IV) analogue of cisplatin even after 5 days of incubation, suggesting their inability to reduce Pt(IV) to Pt(II). Upon addition of an excess of reducing agents such as GSH and ascorbic acid, adducts corresponding initially to [Mets7+PtCl] + and then evolving into…”

Section: Copper Transporters and Chaperonsmentioning

confidence: 99%

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Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

108

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Differential Reactivity of Metal Binding Domains of Copper ATPases towards Cisplatin and Colocalization of Copper and Platinum

Fang

Tian

Yuan

et al. 2018

Chemistry A European J

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The Menkes (MNK) and Wilson (WLN) disease proteins are two P-type ATPases responsible for active Cu efflux. These ATPases are also associated with resistance to cisplatin. In this work, different metal-binding domains (MBDs) of ATPases (9 out of 12 domains) were compared based on their reactivity towards cisplatin. The reaction rates of the MBDs can be largely different; the reaction of MNK6 is about six times faster than that of WLN2. Copper coordination favors the platination of the MBDs to different extents. The rate of platination was generally greater for holo-MBDs than for apo-MBDS (particularly in the case of WLN4 and WLN2); however, it was negligibly affected in the case of MNK6. Interestingly, the platinum binding weakens the Cu coordination, but does not expel the copper ion from MBDs. The latter results nicely explain the inhibitory effect of Cu upon the cisplatin translocation promoted by Cu-ATPases and can help in understanding how copper levels can modulate the sensitivity of cancer cells to platinum chemotherapy.

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Copper binding promotes the interaction of cisplatin with human copper chaperone Atox1

Cited by 40 publications

References 27 publications

Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Differential Reactivity of Metal Binding Domains of Copper ATPases towards Cisplatin and Colocalization of Copper and Platinum

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