The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis
Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:403 |
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| Enthalten in: |
Cancer letters - 403(2017) vom: 10. Sept., Seite 74-85 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kollareddy, Madhu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.09.2017 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.canlet.2017.05.027 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Kollareddy, Madhu |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis |
| 264 | 1 | |c 2017 | |
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| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Chemotherapy | |
| 650 | 4 | |a Drug resistance/synergy | |
| 650 | 4 | |a Mitosis | |
| 650 | 4 | |a Neuroblastoma | |
| 650 | 4 | |a YK-4-279 | |
| 650 | 7 | |a Antimitotic Agents |2 NLM | |
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| 650 | 7 | |a Indoles |2 NLM | |
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| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
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| 650 | 7 | |a P88XT4IS4D |2 NLM | |
| 700 | 1 | |a Sherrard, Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Ji Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Szemes, Marianna |e verfasserin |4 aut | |
| 700 | 1 | |a Gallacher, Kelli |e verfasserin |4 aut | |
| 700 | 1 | |a Melegh, Zsombor |e verfasserin |4 aut | |
| 700 | 1 | |a Oltean, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Michaelis, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Cinatl, Jindrich |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Kaidi, Abderrahmane |e verfasserin |4 aut | |
| 700 | 1 | |a Malik, Karim |e verfasserin |4 aut | |
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