Time-Dependent Studies of Oxaliplatin and Other Nucleolar Stress-Inducing Pt(II) Derivatives.

The properties of small molecule Pt(II) compounds that drive specific cellular responses are of interest due to their broad clinical use as chemotherapeutics as well as to provide a better mechanistic understanding of bioinorganic processes. The chemotherapeutic compound cisplatin causes cell death through DNA damage, while oxaliplatin may induce cell death through inhibition of ribosome biogenesis, also referred to as nucleolar stress induction. Previous work has found a subset of oxaliplatin derivatives that cause nucleolar stress at 24 h drug treatment.

Early nucleolar responses differentiate mechanisms of cell death induced by oxaliplatin and cisplatin.

Recent reports provide evidence that the platinum chemotherapeutic oxaliplatin causes cell death via ribosome biogenesis stress, while cisplatin causes cell death via the DNA damage response (DDR). Underlying differences in mechanisms that might initiate disparate routes to cell death by these two broadly used platinum compounds have not yet been carefully explored. Additionally, prior studies had demonstrated that cisplatin can also inhibit ribosome biogenesis.

Nucleolar Stress Induction by Oxaliplatin and Derivatives.

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.

Monofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique?

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.