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 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.
Verfasserangaben: | Monika RaabORCiD, Mourad SanhajiORCiDGND, Shengtao Zhou, Franz RödelORCiDGND, Ahmed el- Balat, Sven BeckerORCiDGND, Klaus StrebhardtORCiD |
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URN: | urn:nbn:de:hebis:30:3-485086 |
DOI: | https://doi.org/10.1016/j.neo.2019.01.007 |
ISSN: | 1522-8002 |
ISSN: | 1476-5586 |
Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/30851646 |
Titel des übergeordneten Werkes (Englisch): | Neoplasia |
Verlag: | Stockton Press |
Verlagsort: | Basingstoke |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Jahr der Fertigstellung: | 2019 |
Datum der Erstveröffentlichung: | 07.03.2019 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 12.03.2019 |
Jahrgang: | 21 |
Ausgabe / Heft: | 4 |
Seitenzahl: | 13 |
Erste Seite: | 363 |
Letzte Seite: | 375 |
Bemerkung: | © 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 |
Institute: | Medizin / Medizin |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Lizenz (Deutsch): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |