Details

Autor(en) / Beteiligte

• Weiß, Lilly Magdalena
• Hugle, Manuela
• Romero, Sarah
• Fulda, Simone

Titel

Synergistic induction of apoptosis by a polo‐like kinase 1 inhibitor and microtubule‐interfering drugs in E wing sarcoma cells

Ist Teil von

• International journal of cancer, 2016-01, Vol.138 (2), p.497-506

Erscheinungsjahr

2016

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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. What's new? PLK1 is overexpressed in many cancers. Inhibitors of PLK1 such as BI 6727 are in clinical trials for several types of cancer, but preclinical results in pediatric tumors have so far been disappointing. In this study, the authors found that combining BI 6727 with drugs that interfere with microtubules had a synergistic effect, inducing significant apoptosis in Ewing sarcoma cells. This type of combination therapy may thus provide a promising new strategy for the treatment of Ewing sarcoma.