Oncotarget

Research Papers:

Eribulin alone or in combination with the PLK1 inhibitor BI 6727 triggers intrinsic apoptosis in Ewing sarcoma cell lines

Lilly Magdalena Weiß, Manuela Hugle and Simone Fulda _

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Oncotarget. 2017; 8:52445-52456. https://doi.org/10.18632/oncotarget.17190

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Abstract

Lilly Magdalena Weiß1,2,3, Manuela Hugle1 and Simone Fulda1,2,3

1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Simone Fulda, email: simone.fulda@kgu.de

Keywords: apoptosis, eribulin, PLK1, Ewing sarcoma

Received: January 12, 2017     Accepted: March 02, 2017     Published: April 18, 2017

ABSTRACT

In this study, we investigated the molecular mechanisms of eribulin-induced cell death and its therapeutic potential in combination with the PLK1 inhibitor BI 6727 in Ewing sarcoma (ES). Here, we show that eribulin triggers cell death in a dose-dependent manner in a panel of ES cell lines. In addition, eribulin at subtoxic, low nanomolar concentrations acts in concert with BI 6727 to induce cell death and to suppress long-term clonogenic survival. Mechanistic studies reveal that eribulin monotherapy at cytotoxic concentrations and co-treatment with eribulin at subtoxic concentrations together with BI 6727 arrest cells in the M phase of the cell cycle prior to the onset of cell death. This mitotic arrest is followed by increased phosphorylation of BCL-2 and BCL-xL as well as downregulation of MCL-1, suggesting inactivation of these antiapoptotic BCL-2 family proteins. Consistently, eribulin monotherapy and eribulin/BI 6727 co-treatment trigger activation of BAX, a key proapoptotic BCL-2 family protein, and increase proteolytic activation of caspase-9 and -3. Importantly, overexpression of BCL-2 or addition of the broad-range caspase inhibitor zVAD.fmk significantly rescue eribulin- as well as eribulin/BI 6727-induced cell death. Together, these findings demonstrate that eribulin induces cell death via the intrinsic pathway of apoptosis in ES cells, both alone at cytotoxic concentrations and in combination with BI 6727 at subtoxic concentrations. Thus, our study highlights the therapeutic potential of eribulin for the treatment of ES alone or in rational combination therapies.


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