A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe
Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs ta...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2161 |
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| author | Mykola Zdioruk Andrew Want Anna Mietelska-Porowska Katarzyna Laskowska-Kaszub Joanna Wojsiat Agata Klejman Ewelina Użarowska Paulina Koza Sylwia Olejniczak Stanislaw Pikul Witold Konopka Jakub Golab Urszula Wojda |
| author_facet | Mykola Zdioruk Andrew Want Anna Mietelska-Porowska Katarzyna Laskowska-Kaszub Joanna Wojsiat Agata Klejman Ewelina Użarowska Paulina Koza Sylwia Olejniczak Stanislaw Pikul Witold Konopka Jakub Golab Urszula Wojda |
| author_sort | Mykola Zdioruk |
| collection | DOAJ |
| description | Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells. |
| first_indexed | 2024-03-10T17:58:56Z |
| format | Article |
| id | doaj.art-ccb63e1e41af4441930104012dc39f55 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T17:58:56Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ccb63e1e41af4441930104012dc39f552023-11-20T09:02:03ZengMDPI AGCancers2072-66942020-08-01128216110.3390/cancers12082161A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic CatastropheMykola Zdioruk0Andrew Want1Anna Mietelska-Porowska2Katarzyna Laskowska-Kaszub3Joanna Wojsiat4Agata Klejman5Ewelina Użarowska6Paulina Koza7Sylwia Olejniczak8Stanislaw Pikul9Witold Konopka10Jakub Golab11Urszula Wojda12Laboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandLaboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandOncoArendi Therapeutics, 02-089 Warsaw, PolandOncoArendi Therapeutics, 02-089 Warsaw, PolandLaboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandDepartment of Immunology, Medical University of Warsaw, 02-091 Warsaw, PolandLaboratory of Preclinical Testing of Higher Standards, Nencki Institute of Experimental Biology, Polish Academy of Science, 02-093 Warsaw, PolandInduction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.https://www.mdpi.com/2072-6694/12/8/2161cancerchemotherapeuticmicrotubule-poisonvincristinemitotic catastrophenon-apoptotic cell death |
| spellingShingle | Mykola Zdioruk Andrew Want Anna Mietelska-Porowska Katarzyna Laskowska-Kaszub Joanna Wojsiat Agata Klejman Ewelina Użarowska Paulina Koza Sylwia Olejniczak Stanislaw Pikul Witold Konopka Jakub Golab Urszula Wojda A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe Cancers cancer chemotherapeutic microtubule-poison vincristine mitotic catastrophe non-apoptotic cell death |
| title | A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe |
| title_full | A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe |
| title_fullStr | A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe |
| title_full_unstemmed | A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe |
| title_short | A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe |
| title_sort | new inhibitor of tubulin polymerization kills multiple cancer cell types and reveals p21 mediated mechanism determining cell death after mitotic catastrophe |
| topic | cancer chemotherapeutic microtubule-poison vincristine mitotic catastrophe non-apoptotic cell death |
| url | https://www.mdpi.com/2072-6694/12/8/2161 |
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