Most research into the widely used class of platinum anticancer drugs such as cisplatin and oxaliplatin has focused on their ability to cause cell death through initiating DNA damage response (DDR) pathways following binding to genomic DNA. Recent studies have revealed unexpected results that certain platinum compounds related to oxaliplatin exert their cytotoxic effects via ribosome biogenesis stress, or nucleolar stress. Our laboratory has tested a panel of small-molecule Pt(II) derivatives to gain insight into the structural requirements necessary for nucleolar stress induction and found a surprising level of sensitivity to ligand size and other properties, suggesting that a relatively specific interaction is disrupted by compounds that cause nucleolar stress. Measurements of rRNA synthesis and processing, DNA damage, and NPM1 and fibrillarin localization were used to further characterize nucleolar stress induction in A549 cells by a selection of compounds. We found that at equivalent doses, oxaliplatin, but not cisplatin, significantly and rapidly inhibited rRNA synthesis by Pol I. Oxaliplatin’s inhibitory effect on rRNA synthesis corresponds with rapid NPM1 redistribution, followed by nucleolar reorganization and formation of nucleolar caps. Cisplatin caused significantly more DNA damage than oxaliplatin at early time points with minimal effects on the nucleolus. Together, these data support a model in which, at clinically relevant doses, cisplatin kills cells via the canonical DDR, and oxaliplatin kills cells via nucleolar stress, specifically including rapid inhibition of rRNA synthesis. The structural requirements for platinum compounds that cause nucleolar stress, including modifications to the diaminocyclohexane ligand, have been narrowed down through studies of several related variants that cause NPM1 relocalization accompanied by loss of rRNA synthesis, with time-dependent effects observed as early as 30 minutes after treatment. Current efforts are focused on determining the molecular mechanism of action of these small molecule platinum compounds that specifically induce nucleolar stress.

Nucleolar stress induced by small-molecule platinum(II) compounds

ACS Spring 2022

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