👤 Christopher H Hendon

Platinum anticancer therapeutics are widely used in a variety of chemotherapy regimens. Recent work has revealed that the cytotoxicity of oxaliplatin and phenanthriplatin is through induction of ribosome biogenesis stress pathways, differentiating them from cisplatin and other compounds that mainly work through DNA damage response mechanisms. To probe the structure-activity relationships in phenanthriplatin's ability to cause nucleolar stress, a series of monofunctional platinum(II) compounds differing in ring number, size and orientation was tested by nucleophosmin (NPM1) relocalization assays using A549 cells. Phenanthriplatin was found to be unique among these compounds in inducing NPM1 relocalization. To decipher underlying reasons, computational predictions of steric bulk, platinum(II) compound surface length and hydrophobicity were performed for all compounds. Of the monofunctional platinum(II) compounds tested, phenanthriplatin has the highest calculated hydrophobicity and volume but does not exhibit the largest distance from platinum(II) to the surface. Thus, spatial orientation and/or hydrophobicity caused by the presence of a third aromatic ring may be significant factors in the ability of phenanthriplatin to cause nucleolar stress. Show less

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. Show less