Subcellular Partitioning of Arsenic Trioxide Revealed by Label-Free Imaging

Song Huang, Kai Chen, Jong-Kai Leung, Paul Guagliardo, Weihua Chen, Wenxin Song, Peta Clode, Jiake Xu, Stephen G. Young, Haibo Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Subcellular partitioning of therapeutic agents is highly relevant to their interactions with target molecules and drug efficacy, but studying subcellular partitioning is an enormous challenge. Here, we describe the application of nanoscale secondary ion mass spectrometry (NanoSIMS) analysis to define the subcellular pharmacokinetics of a cytotoxic chemotherapy drug, arsenic trioxide (ATO). We reasoned that defining the partitioning of ATO would yield valuable insights into the mechanisms underlying ATO efficacy. NanoSIMS imaging made it possible to define the intracellular fate of ATO in a label-free manner-and with high resolution and high sensitivity. Our studies of ATO-treated cells revealed that arsenic accumulates in the nucleolus. After prolonged ATO exposure, similar to 40 nm arsenic- and sulfur-rich protein aggregates appeared in the cell nucleolus, nucleus, and membrane-free compartments in the cytoplasm, and our studies suggested that the partitioning of nanoscale aggregates could be relevant to cell survival. All-trans retinoic acid increased intracellular ATO levels and accelerated the nanoscale aggregate formation in the nucleolus. This study yielded fresh insights into the subcellular pharmacokinetics of an important cancer therapeutic agent and the potential impact of drug partitioning and pharmacokinetics on drug activity.

Original languageEnglish
Pages (from-to)13889-13896
Number of pages8
JournalAnalytical Chemistry
Volume94
Issue number40
DOIs
Publication statusPublished - 11 Oct 2022

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