Abstract 1014: Repurposing the anti-rheumatic gold compound auranofin for high-grade serous ovarian cancer therapy

Abstract

Auranofin (AF) is a gold compound approved in 1985 as a main treatment against rheumatoid arthritis. However, as new anti-rheumatoid agents displaced the use of AF, there have been studies aiming to repurpose the drug to treat other diseases, including cancer. In this study, we investigated the potentiality of AF to impair the growth of high-grade serous ovarian cancer (HGSOC) cells regardless of platinum (CDDP) sensitivity. Preliminary studies utilizing a colorimetric proliferation assay revealed that HGSOC cells that are clinically sensitive (PEO1) or resistant (PEO4) to CDDP-based chemotherapy are both equally sensitive to the growth inhibition induced by AF. The resistant factor estimated for AF-defined as the ratio between IC50 values calculated for the resistant cells and for the sensitive ones—was close to one, suggesting that CDDP-resistant PEO4 cells are equally sensitive to AF than CDDP-sensitive PEO1 cells. As expected, the resistant factor for CDDP was 12-fold higher in PEO4 compared to PEO1. The toxicity of AF against HGSOC cells was further studied exposing PEO1 to various concentrations of AF and assessing cell number, cell viability, and cell cycle traverse after 72 h. Results showed that AF, in a dose-dependent manner, blocked cell proliferation and caused accumulation of cells with hypo-diploid DNA content, suggesting that AF-induced cytotoxicity was associated not only with inhibition of cell proliferation but also with cell death likely driven via apoptosis. We further studied the long-term or residual toxicity of AF by exposing PEO1 cells that were alive, after 72 h treatment with AF, to a clonogenic survival assay. The results clearly demonstrated that even if not dying within 72 h, the cells were affected in a manner not compatible with long-term cell cycle progression as demonstrated by the formation of ‘abortive' colonies (i.e. colonies with few cells that show abnormal phenotypes). Finally, as AF is a pro-oxidant agent, we evaluated whether AF-induced cell death was mediated by oxidative stress by incubating PEO1 cells with AF in the presence or absence of the anti-oxidant N-acetyl-cysteine (NAC). PEO1 cells treated with AF and NAC showed no decrease in cell viability and cell number in comparison to PEO1 cells treated with AF alone. This data reveals that AF most likely induces cell death in a reactive oxygen species (ROS)-dependent manner. In conclusion, our results suggest that AF can equally impair the growth of CDDP-sensitive or -resistant HGSOC cells, and that its toxicity is likely mediated by oxidative stress. Citation Format: Farah H. Abdalbari, Alicia A. Goyeneche, Elvis Martinez-Jaramillo, Siham Sabri, Carlos M. Telleria. Repurposing the anti-rheumatic gold compound auranofin for high-grade serous ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1014.

Cascade-amplification of melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies

“…There is already clinical evidence that VEGF secreted by melanoma cells could recruit MSDCs and Tregs to TME for suppressing the effector function of CTLs, thus contributing to their immune escape. Interestingly, recent reports reveal that AUR could demonstrate potent VEGF suppressing capability through inhibiting ERK1/2-HIF-1α signaling activity in tumor cells [53][54][55] . Indeed, we have carried out transcriptome sequencing on AUR-treated B16F10 cells to screen the treatment-induced impact on various immune-related signaling pathways, and the KEGG enrichment analysis results immediately suggested that AUR treatment pronouncedly inhibited the VEGF signaling pathways (Fig.…”

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia‐positive lymphoid leukemia to tyrosine kinase inhibitors

“…Among the various compounds known to inhibit the TXN system, auranofin (AUR) is the only clinically available drug. Primarily approved for rheumatoid arthritis, AUR has displayed remarkable antitumor characteristics and is now extensively tested as a putative antitumor agent in preclinical and clinical studies (NCT01737502) 13,14 . Although alternative molecular targets have been associated with the anticancer effects of AUR, 15,16 it is widely believed that TXN‐R is the primary target at the low micromolar concentration range 17–19 .…”

“…Primarily approved for rheumatoid arthritis, AUR has displayed remarkable antitumor characteristics and is now extensively tested as a putative antitumor agent in preclinical and clinical studies (NCT01737502). 13 , 14 Although alternative molecular targets have been associated with the anticancer effects of AUR, 15 , 16 it is widely believed that TXN‐R is the primary target at the low micromolar concentration range. 17 , 18 , 19 Notably, AUR showed promising antitumor effects in various B‐cell malignancies, 11 , 12 including B‐ALL.…”