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.