The Disturbance of Anticancer Drug Cisplatin to Cellular Homeostasis of Trace Elements Revealed by ICP-MS and ToF-SIMS

Abstract

Trace elements play important roles in many physiological processes. The disorder in the metabolism and/or homeostasis of the trace elements will cause pathogenic changes, and finally lead to the development of diseases. This present work aimed to investigate the effect of anticancer metallodrug cisplatin on the homeostasis of trace metal elements, iron (Fe), zinc (Zn) and copper (Cu), in both human HEK293 normal cells and A549 lung cancer cells by using inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The levels of trace metal elements in both whole cells and nuclei subjected to cisplatin treatment were measured by ICP-MS, and results showed that accompanying with the increasing concentration of cisplatin, the content of Fe inside whole cells and nuclei of both normal and cancer cells increased, implying that cisplatin may induce ferroptosis, contributing to its anticancer activity. While the level of Cu and Zn in the whole cells increased with increase in cisplatin concentration, the level of Cu and Zn, in particular the latter, in nuclei decreased with increase of cisplatin concentration. These implicate that cisplatin may compete with Zn for binding to metalloproteins in nuclei, leading to efflux of Zn from nucleus. The normalized signal intensity of Fe, Zn, and Cu in single cells detected by ToF-SIMS increased accompanying with increased cisplatin concentration, being in line with that obtained by quantitative ICP-MS on large quantity of cells. These findings provide novel insights into better understanding in the mechanism of action of cisplatin.Trace metal elements, such as iron, zinc, copper, are essential in the human body as they consist of many metalloproteins or enzymes which are involved in vital physiological regulation processes and play crucial roles in maintaining the normal function

Advancements in ToF-SIMS imaging for life sciences

“…ToF-SIMS exhibits exceptional performance in single-cell imaging owing to its high special resolution, specificity, and sensitivity ( Gilmore, 2013 ; Gilmore et al, 2019 ). With its capacity to precisely analyze diverse target molecules in situ , including elements, lipids, and amino acids, ToF-SIMS enables the study of cellular heterogeneity and function at the single-cell level, and has gained tremendous attention in recent years ( Passarelli and Ewing, 2013 ; Wu et al, 2017 ; Jia et al, 2021 ).…”

“…It provides high spatial resolution (tens of nanometer level) and can analyze very small surface areas, down to the micrometer scale ( Kim et al, 2015 ; Wirtz et al, 2015 ). It can detect a wide range of elements, including both metals and non-metals, and can provide information about the chemical bonding and molecular information of the sample surface ( Jia et al, 2021 ; Priebe et al, 2021 ; Priebe and Michler, 2023 ; Zimmermann et al, 2023 ).…”

Elevated N-Glycosylation Contributes to the Cisplatin Resistance of Non-Small Cell Lung Cancer Cells Revealed by Membrane Proteomic and Glycoproteomic Analysis

“…Cell membrane holds multiple membrane carrier proteins (e.g., solute carrier family 22 A1/2/3/4/5, copper transporter 1, volume-regulated anion channels, ATP-binding cassette superfamily), which control the cisplatin uptake and efflux, thereby determining the intracellular drug concentration ( Ishida et al, 2002 ; Wen et al, 2014 ; Harrach and Ciarimboli, 2015 ; Planells-Cases et al, 2015 ; Jia et al, 2021 ). Importantly, most of these membrane proteins undergo post-translational modifications, particularly with various glycans ( Maryon et al, 2007 ; Voss et al, 2014 ).…”