Madhu Kollareddy, Alice Sherrard, Ji Hyun Park, Marianna Szemes, Kelli Gallacher, Zsombor Melegh, Sebastian Oltean, Martin Michaelis, Jindrich Cinatl, Abderrahmane Kaidi, Karim Malik
- Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers.
MetadatenAuthor: | Madhu Kollareddy, Alice Sherrard, Ji Hyun Park, Marianna Szemes, Kelli Gallacher, Zsombor Melegh, Sebastian Oltean, Martin MichaelisORCiDGND, Jindrich CinatlORCiDGND, Abderrahmane Kaidi, Karim Malik |
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URN: | urn:nbn:de:hebis:30:3-447457 |
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DOI: | https://doi.org/10.1016/j.canlet.2017.05.027 |
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ISSN: | 1872-7980 |
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ISSN: | 0304-3835 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28602975 |
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Parent Title (English): | Cancer letters |
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Publisher: | Elsevier Science |
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Place of publication: | Amsterdam [u. a.] |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2017/11/02 |
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Date of first Publication: | 2017/06/07 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/11/02 |
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Tag: | Chemotherapy; Drug resistance/synergy; Mitosis; Neuroblastoma; YK-4-279 |
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Volume: | 403 |
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Page Number: | 12 |
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First Page: | 74 |
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Last Page: | 85 |
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Note: | © 2017 The Author(s). Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
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HeBIS-PPN: | 427891582 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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