Novel Insights into Redox-Based Mechanisms for Auranofin-Induced Rapid Cancer Cell Death

Auranofin (Ridaura (R), AUF) is a gold complex originally approved as an antirheumatic agent that has emerged as a potential candidate for multiple repurposed therapies. The best-studied anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR). However, a number of reports indicate a more complex and multifaceted mode of action for AUF that could be cancer cell type- and dose-dependent. In this study, we observed that AUF displayed variable cytotoxicity in five triple-negative breast cancer cell lines. Using representative MDA-MB-231 cells treated with moderate and cytotoxic doses of AUF, we evidenced that an AUF-mediated TrxR inhibition alone may not be sufficient to induce cell death. Cytotoxic doses of AUF elicited rapid and drastic intracellular oxidative stress affecting the mitochondria, cytoplasm and nucleus. A redoxome proteomics investigation revealed that a short treatment with a cytotoxic dose AUF altered the redox state of a number of cysteines-containing proteins, pointing out that the cell proliferation/cell division/cell cycle and cell-cell adhesion/cytoskeleton structure were the mostly affected pathways. Experimentally, AUF treatment triggered a dose-dependent S-phase arrest and a rapid disintegration of the actin cytoskeleton structure. Our study shows a new spectrum of AUF-induced early effects and should provide novel insights into the complex redox-based mechanisms of this promising anticancer molecule.

Automated summary

Auranofin (AUF) is a gold complex that has shown potential as a repurposed therapy for multiple diseases, including cancer. The main anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR), but other complex and multifaceted modes of action have also been observed. This study found that AUF had variable cytotoxicity in different triple-negative breast cancer cell lines and that TrxR inhibition alone may not be sufficient to induce cell death. Cytotoxic doses of AUF caused oxidative stress and affected various pathways related to cell proliferation, cell cycle, cell-cell adhesion, and cytoskeleton structure. These findings provide new insights into the redox-based mechanisms of AUF as an anticancer molecule.