Universität zu Köln

Schott, Sarah ORCID: 0000-0002-1714-1147, Wimberger, Pauline, Klink, Barbara, Gruetzmann, Konrad, Puppe, Julian, Wauer, Ulrike Sophie, Klotz, Daniel Martin, Schroeck, Evelin and Kuhlmann, Jan Dominik (2017). The conjugated antimetabolite 5-FdU-ECyd and its cellular and molecular effects on platinum-sensitive vs. -resistant ovarian cancer cells in vitro. Oncotarget, 8 (44). S. 76935 - 76949. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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-5fluorouridine (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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schott, Sarah UNSPECIFIED orcid.org/0000-0002-1714-1147 UNSPECIFIED Wimberger, Pauline UNSPECIFIED UNSPECIFIED UNSPECIFIED Klink, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruetzmann, Konrad UNSPECIFIED UNSPECIFIED UNSPECIFIED Puppe, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wauer, Ulrike Sophie UNSPECIFIED UNSPECIFIED UNSPECIFIED Klotz, Daniel Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeck, Evelin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuhlmann, Jan Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-217303
DOI:	10.18632/oncotarget.20260
Journal or Publication Title:	Oncotarget
Volume:	8
Number:	44
Page Range:	S. 76935 - 76949
Date:	2017
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE; CISPLATIN; FOS; RECURRENT; BEVACIZUMAB; ACTIVATION; MECHANISMS; INDUCTION; TAS-106; REPAIR Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21730