Oxaliplatin disrupts nucleolar function through biophysical disintegration

SUMMARY

Platinum (Pt) compounds such as oxaliplatin are among the most commonly prescribed anti-cancer drugs. Despite their considerable clinical impact, the molecular basis of platinum cytotoxicity and cancer specificity remain unclear. Here we show that oxaliplatin, a backbone for the treatment of colorectal cancer, causes liquid-liquid demixing of nucleoli at clinically relevant concentrations. Our data suggest that this biophysical defect leads to cell-cycle arrest, shutdown of Pol I-mediated transcription, and ultimately cell death. We propose that instead of targeting a single molecule, oxaliplatin preferentially partitions into nucleoli, where it modifies nucleolar RNA and proteins. This mechanism provides a general approach for drugging the increasing number of cellular processes linked to biomolecular condensates.

Graphical abstract

In brief

Schmidt et al. report on the mechanism of the anti-cancer drug oxaliplatin. They find that oxaliplatin affects phase separation, disintegrates nucleoli, and indirectly inhibits rRNA synthesis. This suggests that targeting the nucleolus with drugs modulating its biophysical properties is a viable anti-cancer strategy.