Open AccessMonofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique?
Author(s) -
Christine E. McDevitt,
Matthew V. Yglesias,
Austin Mroz,
Emily Sutton,
Min Yang,
Christopher H. Hendon,
Victoria J. DeRose
Publication year - 2019
Publication title -
jbic. journal of biological inorganic chemistry/jbic, journal of biological and inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.802
H-Index - 101
eISSN - 1432-1327
pISSN - 0949-8257
DOI - 10.1007/s00775-019-01707-9
Subject(s) - chemistry , platinum , cisplatin , cytotoxicity , stereochemistry , ribosome biogenesis , biochemistry , biophysics , in vitro , ribosome , rna , medicine , surgery , chemotherapy , biology , gene , catalysis
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.