Research Papers:
The conjugated antimetabolite 5-FdU-ECyd and its cellular and molecular effects on platinum-sensitive vs. -resistant ovarian cancer cells in vitro
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Abstract
Sarah Schott1,2,3,*, Pauline Wimberger2,4,5,*, Barbara Klink2,5,6, Konrad Grützmann2,5, Julian Puppe7, Ulrike Sophie Wauer2,4,5, Daniel Martin Klotz2,4,5, Evelin Schröck2,5,6 and Jan Dominik Kuhlmann2,4,5
1Department of Gynecology and Obstetrics, University Hospital of Heidelberg, Heidelberg, Germany
2German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
3National Center for Tumor Diseases (NCT), Heidelberg, Germany
4Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
5National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
6Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
7Department of Gynecology and Obstetrics, University Hospital of Cologne, Cologne, Germany
*These authors have contributed equally to the underlying study
Correspondence to:
Jan Dominik Kuhlmann, email: [email protected]
Keywords: ovarian cancer, 5-FdU-ECyd, duplex-prodrugs, TAS106, platinum-resistance
Received: May 25, 2017 Accepted: June 29, 2017 Published: August 14, 2017
ABSTRACT
Background: Resistance to platinum-based chemotherapy is a clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, innovative drugs against platinum-resistance are urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and cleaved into active cytostatic metabolites. We explore the activity of the duplex-prodrug 5-FdU-ECyd, covalently linking 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), on platinum-resistant OC cells.
Methods: In vitro assays and RNA-Sequencing were applied for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis and independent platinum-resistant Skov-3-IP OC cells.
Results: Nano molar 5-FdU-ECyd concentrations induced a rapid dose-dependent decline of cell viability in platinum-sensitive and -resistant OC cells. The effect of 5-FdU-ECyd was accompanied by the formation of DNA double strand breaks and apoptosis induction, indicated by a strong increase of pro-apoptotic molecular markers. Moreover, 5-FdU-ECyd efficiently decreased migration of platinum-resistant OC cells and inhibited clonogenic or spheroidal growth. Transcriptome analysis showed early up-regulation of CDKN1A and c-Fos in both, platinum-resistant and -sensitive cells after 5-FdU-ECyd treatment and de-regulation of distinct cellular pathways involved in cell cycle regulation, apoptosis, DNA-damage response and RNA-metabolism. Combined treatment of 5-FdU-ECyd and cisplatin did not show a synergistic cellular response, suggesting the potential use of 5-FdU-ECyd as a monotherapeutic agent.
Conclusion: Our data provide novel mechanistic insight into the anti-tumor effect of 5-FdU-ECyd and we hypothesize that this duplex-prodrug could be a promising therapeutic option for OC patients with resistance to platinum-based chemotherapy.
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