Nucleolar Stress Induction by Oxaliplatin and Derivatives.

Emily C Sutton, Christine E McDevitt, Jack Y Prochnau, Matthew V Yglesias, Austin M Mroz, Min Chieh Yang, Rachael M Cunningham, Christopher H Hendon, Victoria J DeRose

Journal of the American Chemical Society 2019 Nov 20

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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.

Citation

Emily C Sutton, Christine E McDevitt, Jack Y Prochnau, Matthew V Yglesias, Austin M Mroz, Min Chieh Yang, Rachael M Cunningham, Christopher H Hendon, Victoria J DeRose. Nucleolar Stress Induction by Oxaliplatin and Derivatives. Journal of the American Chemical Society. 2019 Nov 20;141(46):18411-18415