Subcellular Partitioning of Arsenic Trioxide Revealed by Label-Free Imaging.
Anal Chem
; 94(40): 13889-13896, 2022 10 11.
Article
em En
| MEDLINE
| ID: mdl-36189785
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 mannerâand with high resolution and high sensitivity. Our studies of ATO-treated cells revealed that arsenic accumulates in the nucleolus. After prolonged ATO exposure, â¼40 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Arsênio
/
Arsenicais
/
Leucemia Promielocítica Aguda
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article