Abstract
High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.
Highlights
Epithelial ovarian cancer (EOC), the most lethal type of gynecological cancer, is the fourth leading cause of cancer-associated mortality among women in the USA and Europe [1,2]
As differences the steroid metabolism between platinum-sensitive and -resistant High-grade serous ovarian cancer (HGSOC) cells have not been in theinsteroid metabolism between platinum-sensitive and -resistant HGSOC cells have not been investigated yet, the present study screened the formation of DHEA and E1 biotransformation investigated yet, the present study screened the formation of DHEA and E1 biotransformation products products in four recently established and two commercially available HGSOC cell lines as in vitro in four recently established and two commercially available HGSOC cell lines as in vitro models models for HGSOC
Resistance against platinum-based drugs is a main obstacle in the therapy of HGSOC patients
Summary
Epithelial ovarian cancer (EOC), the most lethal type of gynecological cancer, is the fourth leading cause of cancer-associated mortality among women in the USA and Europe [1,2]. The total incidence in 2018 was relatively low with 300,000 new cases worldwide, its fatality rate is high, as the number of deaths was almost 200,000 in the same year [3]. The most frequent form of EOC, accounting for almost 75% of all cases, is high-grade serous ovarian cancer (HGSOC), an aggressive subtype that shows only a 30% to 40% five-year survival rate for all patients [4,5,6]. Cytoreductive debulking surgery and platinum-based chemotherapy is the standard for HGSOC treatment [7,8]. Novel therapeutic approaches with targeted therapeutics, including poly ADP-ribose)-polymerase 1 (PARP) and vascular endothelial growth factor (VEGF) inhibitors can increase cytotoxic activity and apoptosis in platinum-resistant
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