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Synergistic induction of apoptosis by a polo‐like kinase 1 inhibitor and microtubule‐interfering drugs in E wing sarcoma cells
Author(s) -
Weiß Lilly Magdalena,
Hugle Manuela,
Romero Sarah,
Fulda Simone
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29725
Subject(s) - plk1 , apoptosis , kinase , tubulin , polo like kinase , vinorelbine , mitosis , staurosporine , biology , cancer research , microtubule , pharmacology , microbiology and biotechnology , protein kinase a , cell cycle , biochemistry , chemotherapy , cisplatin , genetics
Since polo‐like kinase 1 (PLK1) is highly expressed in Ewing sarcoma (ES), we evaluated the therapeutic potential of the PLK1 inhibitor BI 6727. Here, we identify a synergistic induction of apoptosis by BI 6727 and several microtubule‐interfering drugs in ES cells, including vincristine (VCR), vinblastine (VBL), vinorelbine (VNR) and eribulin. Synergistic drug interaction is confirmed by calculation of combination index (CI). Also, BI 6727 and VCR act in concert to reduce long‐term clonogenic survival. Mechanistically, BI 6727/VCR co‐treatment cooperates to trigger mitotic arrest, phosphorylation of BCL‐2 and BCL‐X L and downregulation of MCL‐1. This inactivation of anti‐apoptotic BCL‐2 family proteins in turn promotes activation of BAX and BAK, activation of caspase‐9 and ‐3 and caspase‐dependent apoptosis. Overexpression of BCL‐2 or simultaneous knockdown of BAX and BAK significantly rescue BI 6727/VCR‐induced apoptosis, indicating that engagement of the mitochondrial pathway is critical for BI 6727/VCR‐mediated apoptosis. The clinical relevance of PLK1 inhibitor‐based combination therapies is underscored by the fact that BI 6727 is currently evaluated in phase I clinical trials in childhood cancer. In conclusion, PLK1 inhibitors such as BI 6727 may provide a new strategy to chemosensitize ES.