Open AccessNucleolar Stress Induction by Oxaliplatin and Derivatives
Author(s) -
Emily Sutton,
Christine E. McDevitt,
Jack Y Prochnau,
Matthew V. Yglesias,
Austin Mroz,
Min Yang,
Rachael Cunningham,
Christopher H. Hendon,
Victoria J. DeRose
Publication year - 2019
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b10319
Subject(s) - chemistry , oxaliplatin , nucleophosmin , cisplatin , oxalate , ligand (biochemistry) , redistribution (election) , cytotoxicity , platinum , stereochemistry , biochemistry , in vitro , organic chemistry , receptor , medicine , cancer , chemotherapy , colorectal cancer , politics , political science , law , gene , catalysis
Platinum(II) compounds are a critical class of chemotherapeutic agents. Recent studies have highlighted the ability of a subset of Pt(II) compounds, including oxaliplatin but not cisplatin, to induce cytotoxicity via nucleolar stress rather than a canonical DNA damage response. In this study, influential properties of Pt(II) compounds were investigated using redistribution of nucleophosmin (NPM1) as a marker of nucleolar stress. NPM1 assays were coupled to calculated and measured properties such as compound size and hydrophobicity. The oxalate leaving group of oxaliplatin is not required for NPM1 redistribution. Interestingly, although changes in diaminocyclohexane (DACH) ligand ring size and aromaticity can be tolerated, ring orientation appears important for stress induction. The specificity of ligand requirements provides insight into the striking ability of only certain Pt(II) compounds to activate nucleolar processes.