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Dear Colleagues,

Epithelial ovarian cancer is a devastating disease leading to high mortality due to a lack of early diagnosis and failure of long-term treatment strategies. Since the introduction of cytoreductive surgery and platinum–taxane combination treatment in the 1980–90s, there have been no significant breakthroughs influencing the overall survival of patients except for the use of PARP inhibitors in BRCA1 deficient individuals. To make matters more complex, this disease is not unitary; conversely, it is represented by multiple malignancies pathologically defined as high-grade serous, low-grade serous, mucinous, clear cell, and endometrioid carcinoma. The burden of this disease is highly prevalent, as demonstrated by the fact that the overall survival has not significantly changed in decades.

In this Special Issue of Cancers, we welcome original research articles or comprehensive review articles focusing on research related to novel therapeutic approaches for all histotypes of epithelial ovarian cancer, including, among others, novel target therapeutics, combination drug therapies, repurposed drugs, immunotherapies, PARP inhibitors and antiangiogenic drugs, natural products, and synthetic anti-cancer compounds.

Dr. Carlos M. Telleria
Guest Editor

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Keywords

ovarian cancer
cancer therapy
drug repurposing
combination therapy
Epithelial ovarian cancer

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23 pages, 5665 KiB

Open AccessArticle

Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells

by Farah H. Abdalbari, Elvis Martinez-Jaramillo, Benjamin N. Forgie, Estelle Tran, Edith Zorychta, Alicia A. Goyeneche, Siham Sabri and Carlos M. Telleria

Cancers 2023, 15(21), 5136; https://doi.org/10.3390/cancers15215136 - 25 Oct 2023

Cited by 2 | Viewed by 1353

Abstract

High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets for Ovarian Cancer)

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