Blocking mitotic exit of ovarian cancer cells by pharmaceutical inhibition of the anaphase-promoting complex reduces chromosomal instability

Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instabi
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
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Metadaten
Author:Monika Raab, Mourad Sanhaji, Shengtao Zhou, Franz Rödel, Ahmed el- Balat, Sven Becker, Klaus Strebhardt
URN:urn:nbn:de:hebis:30:3-485086
DOI:http://dx.doi.org/10.1016/j.neo.2019.01.007
ISSN:1522-8002
ISSN:1476-5586
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30851646
Parent Title (English):Neoplasia
Publisher:Stockton Press
Place of publication:Basingstoke
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/03/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/12
Volume:21
Issue:4
Pagenumber:13
First Page:363
Last Page:375
Note:
© 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).1476-5586
HeBIS PPN:448050145
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0

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