Mass spectrometry techniques for imaging and detection of metallodrugs

Theiner, Sarah; Schoeberl, Anna; Schweikert, Andreas; Keppler, Bernhard K.; Koellensperger, Gunda

doi:10.1016/j.cbpa.2020.12.005

Cited by 33 publications

(22 citation statements)

References 78 publications

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“…Here, we have characterized the pattern of oxaliplatin accumulation in tumor tissue from CRC patients using elemental imaging technique originally developed in the field of geology and adapted to biological samples 43 . Surprisingly, we realized that the TME is the main tumor compartment retaining oxaliplatin long after the treatment ceased.…”

Section: Discussionmentioning

confidence: 99%

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

et al. 2023

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A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

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Section: Discussionmentioning

confidence: 99%

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

et al. 2023

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“…Analysis of individual cells provides highly valuable information on cell-to-cell variance, especially within an isogenic cell population. Cells display significant heterogeneity in size, individual physiological status, or access to nutrients, and specifically drugs, which can lead to varying metal uptake rates and metal concentrations, which is important in metal drug research and their clinical application [ 105 ]. To understand the biochemical status of the entire cell population under consideration, the biology of individual cells needs to be studied [ 106 ].…”

Section: Single Cell Icp-ms (Sc-icp-ms)mentioning

confidence: 99%

Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level

Michalke

2022

IJMS

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Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe2+, Fe3+, and ferritin-bound iron were introduced. In Wilson’s disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level.

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“…In combination with a time-of-flight-based ICP-MS instrument (ICP-TOFMS), which enables the quasi-simultaneous detection of all elements of the periodic table ( Gundlach-Graham and Günther, 2016 ; Malderen et al, 2016 ), and the labeling of cellular markers using metal-tagged antibodies, introduced by mass cytometry ( Lou et al, 2007 ; Bandura et al, 2009 ; Chang et al, 2017 ), the total amount of platinum per cell and its relationship with the CTR1 receptor together with trace elements can be investigated. The potential of single-cell LA-ICP-MS was already comprehensively described elsewhere ( Theiner et al, 2019 , 2020 , 2021 ; Van Acker et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS

Schoeberl

Gutmann

Theiner

et al. 2022

Front. Mol. Biosci.

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More than a decade ago, studies on cellular cisplatin accumulation via active membrane transport established the role of the high affinity copper uptake protein 1 (CTR1) as a main uptake route besides passive diffusion. In this work, CTR1 expression, cisplatin accumulation and intracellular copper concentration was assessed for single cells revisiting the case of CTR1 in the context of acquired cisplatin resistance. The single-cell workflow designed for in vitro experiments enabled quantitative imaging at resolutions down to 1 µm by laser ablation-inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS). Cisplatin-sensitive ovarian carcinoma cells A2780 as compared to the cisplatin-resistant subline A2780cis were investigated. Intracellular cisplatin and copper levels were absolutely quantified for thousands of individual cells, while for CTR1, relative differences of total CTR1 versus plasma membrane-bound CTR1 were determined. A markedly decreased intracellular cisplatin concentration accompanied by reduced copper concentrations was observed for single A2780cis cells, along with a distinctly reduced (total) CTR1 level as compared to the parental cell model. Interestingly, a significantly different proportion of plasma membrane-bound versus total CTR1 in untreated A2780 as compared to A2780cis cells was observed. This proportion changed in both models upon cisplatin exposure. Statistical analysis revealed a significant correlation between total and plasma membrane-bound CTR1 expression and cisplatin accumulation at the single-cell level in both A2780 and A2780cis cells. Thus, our study recapitulates the crosstalk of copper homeostasis and cisplatin uptake, and also indicates a complex interplay between subcellular CTR1 localization and cellular cisplatin accumulation as a driver for acquired resistance development.

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Mass spectrometry techniques for imaging and detection of metallodrugs

Cited by 33 publications

References 78 publications

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level

The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS

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