Identification of bifunctional GA and AG intrastrand crosslinks formed between cisplatin and DNA

Gupta, Rajesh; Beck, Jennifer L.; Sheil, Margaret M.; Ralph, Stephen F.

doi:10.1016/j.jinorgbio.2004.11.001

Cited by 25 publications

(21 citation statements)

References 37 publications

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“…These results indicate that either the MALDI- TOF is sensitive to non-covalent complexes of cisplatin with the ssDNA or that the kinetics of cisplatin addition for this sequence are very fast compared to the 15 min time it takes to do a MALDI-TOF experiment. Nevertheless, the results provided here and in other studies [6][7][8][9][10] provide good evidence that DNA is damaged by cisplatin. The results here show that a single cisplatin-DNA adduct is the major species formed after 12 h incubation.…”

Section: Resultssupporting

confidence: 73%

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Molecular beacon probes for the detection of cisplatin-induced DNA damage

Shire

Loppnow

2012

Anal Bioanal Chem

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Cisplatin (cis-diamminedichloroplatinum(II)) causes crosslinking of DNA at AG and GG sites in cellular DNA, inhibiting replication, and making it a useful anti-cancer drug. Several techniques have been used previously to detect nucleic acid damage but most of these tools are labour-intensive, time-consuming, and/or expensive. Here, we describe a sensitive, robust, and quantitative tool for detecting cisplatin-induced DNA damage by using fluorescent molecular beacon probes (MB). Our results show a decrease of fluorescence in the presence of cisplatin-induced DNA damage, confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The decrease in fluorescence upon damage scales with the number of AG and GG sites, indicating the ability of MB to quantitatively detect DNA damage by cisplatin.

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Section: Resultssupporting

confidence: 73%

“…1) is one of the anti-tumor drugs used to treat testicular, ovarian [6], neck, head, bladder, and small lung cancers [7,8].…”

Section: Introductionmentioning

confidence: 99%

Molecular beacon probes for the detection of cisplatin-induced DNA damage

Shire

Loppnow

2012

Anal Bioanal Chem

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“…Cisplatin undergoes aquation to give mainly the monoaqua complex, cis-[Pt(NH 3 ) 2 1 þ ) is far more easily substituted than Cl À by the N(7)-atoms of guanine or adenine forming a monofunctional adduct [42] [47] [48]. The monofunctional adducts subsequently react with a second nucleophile forming primarily intrastrand adducts [41] [49] [50]. Substitution at the amine N-atom inhibits the ring closure to the bifunctional adduct [51].…”

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confidence: 99%

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Ahmad

2010

Chemistry & Biodiversity

190

176

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Platinum-based compounds are widely used as chemotherapeutics for the treatment of a variety of cancers. The anticancer activity of cisplatin and other platinum drugs is believed to arise from their interaction with DNA. Several cellular pathways are activated in response to this interaction, which include recognition by high-mobility group and repair proteins, translesion synthesis by polymerases, and induction of apoptosis. The apoptotic process is regulated by activation of caspases, p53 gene, and several proapoptotic and antiapoptotic proteins. Such cellular processing eventually leads to an inhibition of the replication or transcription machinery of the cell. Deactivation of platinum drugs by thiols, increased nucleotide excision repair of Pt-DNA adducts, decreased mismatch repair, and defective apoptosis result in resistance to platinum therapy. The differences in cytotoxicity of various platinum complexes are attributed to the differential recognition of their adducts by cellular proteins. Cisplatin and oxaliplatin both produce mainly 1,2-GG intrastrand cross-links as major adducts, but oxaliplatin is found to be more active particularly against cisplatin-resistant tumor cells. Mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these two agents. This review describes the formation of Pt-DNA adducts, their interaction with cellular components, and biological effects of this interaction.

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“…As expected, the nature of the adducts was found to be highly dependent on the nature of the ligands on the however, GG and AG sequences have appeared as favourite binding sites. [68] It is worth mentioning that, in general, the "bottom-up" approach is hampered by the use of enzymes such as exonucleases, which cannot cleave most oligonucleotides that have been modified by metallodrugs and might consequently lead to an incomplete set of data. Moreover, binding of Pt complexes to the enzymes in the sample may also interfere with DNA adduct formation.…”

Section: Platinum Complexesmentioning

confidence: 99%

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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Identification of bifunctional GA and AG intrastrand crosslinks formed between cisplatin and DNA

Cited by 25 publications

References 37 publications

Molecular beacon probes for the detection of cisplatin-induced DNA damage

Molecular beacon probes for the detection of cisplatin-induced DNA damage

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

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

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