Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability.

Abstract

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.

• Authors: Monika Raab, Mourad Sanhaji, Shengtao Zhou, Franz Rödel, Ahmed El-Balat, Sven Becker, Klaus Strebhardt
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 21 Issue 4 Pg. 363-375 (04 2019) ISSN: 1476-5586 [Electronic] United States
• PMID: 30851646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biomarkers
• Cell Cycle Proteins
• Proto-Oncogene Proteins
• Anaphase-Promoting Complex-Cyclosome
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• Paclitaxel

Topics

• Anaphase-Promoting Complex-Cyclosome (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers
• Cell Cycle (drug effects)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Chromosomal Instability (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression
• Humans
• Immunohistochemistry
• Mitosis (drug effects, genetics)
• Ovarian Neoplasms (genetics, metabolism, mortality)
• Paclitaxel (pharmacology)
• Prognosis
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)