Abstract 4066: Anticancer effects of the gold complex auranofin on high-grade serous ovarian cancer cells

Abstract

Abstract High-grade serous ovarian cancer (HGSOC) is the 11th most common cancer-causing death in women. HGSOC is treated with platinum (Pt)-based chemotherapy, to which patients develop resistance over time, leaving them with very limited therapeutic options. Thus, new treatments are needed for these patients. In the present work, we provide evidence for the in vitro anti-HGSOC efficacy of the gold complex auranofin (AUF), a compound approved in the clinic in the 1980’s as an anti-rheumatic agent. AUF targets thioredoxin reductase 1 (TrxR1), which is overexpressed in many cancers, including ovarian cancer. Using the Kaplan-Meir plotter database we analyzed that high expression of TrxR1 predicted poor overall survival, suggesting that TrxR1 plays an important role in ovarian cancer progression. We show that AUF impairs the growth of HGSOC cells regardless of Pt sensitivity. HGSOC cells obtained from the same patient when it was clinically sensitive (PEO1) or resistant (PEO4) to Pt-based chemotherapy, were both equally sensitive to the growth inhibition induced by the gold complex in a concentration-dependent manner when using an MTT reduction assay. The toxicity of AUF against HGSOC cells was further studied exposing PEO1 cells to the compound and assessing cell number, cell viability, and cell cycle traverse. Results showed that AUF blocked cell proliferation, reduced viability, and caused accumulation of cells with hypo-diploid DNA content, suggesting a likely apoptosis-mediated cell death mechanism. We confirmed that AUF-triggered lethality was driven by apoptosis by measuring the accumulation of Annexin V positive/7-AAD negative cells via flow cytometry. We also found out that the lethality of AUF required the induction of oxidative stress because the effect was prevented by the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine. We further show that AUF-induced ROS production is associated with the generation of DNA damage as denoted by the increase in the phosphorylation of the Ser-139 residue of the histone variant H2AX by western blotting thus signaling a genotoxic endpoint. Finally, we generated evidence that the combination of AUF and the Pt agent cisplatin (CDDP) is more potent than either drug alone in inducing lethality in PEO4 cells isolated from a patient when Pt-resistant. In summary, we provide proof-of-principle that the TrxR1 inhibitor AUF impairs the survival capacity of HGSOC cells regardless of their Pt sensitivities, triggering a program of apoptosis induced by oxidative stress that is associated with DNA damage; such toxicity is enhanced when AUF is combined with CDDP. The novelty of this work for cancer research in general and HGSOC in particular is that, as AUF is clinically approved to treat arthritis-related conditions, the compound can be rapidly repositioned as a consolidation therapy following Pt-based standard of care and/or overcome Pt resistant disease. Citation Format: Farah H. Abdalbari, Alicia A. Goyeneche, Elvis M. Jaramillo, Siham Sabri, Carlos M. Telleria. Anticancer effects of the gold complex auranofin on high-grade serous ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4066.