TY  - JOUR
A1  - Raab, Monika
A1  - Sanhaji, Mourad
A1  - Zhou, Shengtao
A1  - Rödel, Franz
A1  - Balat, Ahmed el-
A1  - Becker, Sven
A1  - Strebhardt, Klaus
T1  - Blocking mitotic exit of ovarian cancer cells by pharmaceutical inhibition of the anaphase-promoting complex reduces chromosomal instability
T2  - Neoplasia
N2  - 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.
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48508
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-485086
SN  - 1522-8002
SN  - 1476-5586
N1  - © 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
VL  - 21
IS  - 4
SP  - 363
EP  - 375
PB  - Stockton Press
CY  - Basingstoke
ER  -