Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Cancers

Monika Fritzer-Szekeres¹  Anastasia Meshcheryakova²  Diana Mechtcheriakova²  Theresia Thalhammer²  Stefan Poschner³  Walter Jäger³  Judith Wackerlig⁴  Renata Pavlič⁵  TeaLanišnik Rižner⁵  DanCacsire Castillo-Tong⁶  Andrea Wolf⁶  Isabel von der Decken⁶ 

[1] Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria;Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria;Division of Drug Design and Medicinal Chemistry, Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria;Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria;

关键词: high-grade serous ovarian cancer;    steroid hormones;    metabolomics;    lc-hrms;    carboplatin resistance;    interleukin-6;   

DOI  :  10.3390/cancers12020279

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown