Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Ravera, Mauro; Gabano, Elisabetta; Zanellato, Ilaria; Bonarrigo, Ilaria; Alessio, Manuela; Arnesano, Fabio; Galliani, Angela; Natile, Giovanni; Osella, Domenico

doi:10.1016/j.jinorgbio.2015.05.012

Cited by 46 publications

(37 citation statements)

References 70 publications

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“…37,43,48 Furthermore, as expected, the A2780cis cells did not show cisplatininduced apoptosis. 17,46 According to all these results, cisplatin-induced adduct levels depended on the intracellular Pt content within each cell line, but not necessarily when all of the cell lines were considered together.…”

Section: Discussionsupporting

confidence: 72%

“…46,47 On the other hand, the lack of differences in cisplatin adducts between AT-0 and AT-1 times not only for the A2780 cells but also for the A549 and A2780cis cells (all repair active cells), demonstrated that there is an equilibrium between adducts being repaired/removed and new adducts being formed by the remaining intracellular cisplatin, at least in the 1 h time lapse studied, as suggested before. 48 Besides, the repair/removal of cisplatininduced DNA adducts in these cells seemed to be a relatively slow process, as described for A2780 23 and the other cells; 8,23,49 however, it is important to address that no adducts were detected 24 h after the end of treatment (data not shown).…”

Section: Discussionmentioning

confidence: 90%

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Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

et al. 2017

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Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 mM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure. Significance to metallomicsKnowledge about cisplatin as a chemotherapy drug is extensive, including information about the several processes that contribute to its resistance, the main problem of using this chemical. However, this knowledge and information does not yet allow the early identification of resistant tumors/patients, one of the most desired aims of clinicians. In this work we have developed a model that might allow the early detection of chemical resistance and, more importantly, might do so mostly regardless of the resistance mechanism involved, because it determines the dynamics of adduct induction/repair, considering chemical influx/efflux and induced genomic instability.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 90%

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

et al. 2017

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“…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%

“…It is worth mentioning that the reduced Pt(II) species underwent immediate loss of both ammine ligands, indicating most likely replacement by Met residues of the peptide. [194] In the case of MNK1, the addition of reducing agents led to the precipitation of the protein thus making the analysis by MS impossible. The main conclusion drawn for this study was that Pt(IV) prodrugs have a different reactivity than cisplatin towards copper transporters, suggesting a different transport mechanism, potentially rather via passive diffusion.…”

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

105

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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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Contribution of Base Damages to the Molecular Radiosensitization Mechanism of Platinum Chemotherapeutic Drugs

et al. 2019

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The measurement of clustered damages in Pt‐chemotherapeutic‐drugs‐DNA complexes induced by low‐energy (0‐30 eV) electrons (LEEs) may provide further understanding of the synergy mechanism in cancer treatment with concomitant chemoradiation therapy (CRT). Five‐monolayer films of Pt‐DNA complexes, containing cisplatin, carboplatin and oxaliplatin with ratio 5:1 were irradiated with mono‐energetic electrons of 10 eV, the most prominent energy for bond dissociation by LEE impact. Damages to plasmid DNA including crosslinks, SSBs, DSBs and the loss of the supercoiled configuration were analyzed by the electrophoresis. Base damages (BDs) occurring within two turns of DNA helix were detected by the treatment of E. coli base excision repair endonuclease (Nth and Fpg). The total DNA damages to Pt‐DNA complexes was found to be 350 ± 42, 296 ± 45 and 434 ± 46 ×10−15 electron−1molecule−1, respectively, while the percentages of BDs in this total were 56%, 54% and 60%, respectively. Compared to unmodified DNA, binding of Pt‐drugs to DNA increased BDs by factors of 1.9, 1.6 and 2.6, respectively, which partly resulted in significant enhancements of potentially lethal lesions (i. e., crosslinks, double strand breaks (DSBs) and non‐DSB cluster damages). These results reveal the significant role that LEEs play in the formation of clustered DNA damages related to BDs, which are expected to contribute to the higher efficacy of cancer treatment by CRT with the Pt‐drugs investigated.

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Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Cited by 46 publications

References 70 publications

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

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

Contribution of Base Damages to the Molecular Radiosensitization Mechanism of Platinum Chemotherapeutic Drugs

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