A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe
| Autor: | Sylwia Olejniczak, Anna Mietelska-Porowska, Urszula Wojda, Jakub Golab, Katarzyna Laskowska-Kaszub, Stanislaw Pikul, Mykola Zdioruk, Andrew Want, Agata Klejman, Paulina Koza, Joanna Wojsiat, Witold Konopka, Ewelina Użarowska |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
p53 Cancer Research Programmed cell death chemotherapeutic Aurora B kinase lcsh:RC254-282 vincristine Article 03 medical and health sciences non-apoptotic cell death 0302 clinical medicine Microtubule cancer Mitotic catastrophe mitotic catastrophe microtubule-poison Cyclin-dependent kinase 1 biology p21 Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell biology Spindle checkpoint 030104 developmental biology Tubulin Oncology 030220 oncology & carcinogenesis Cancer cell biology.protein |
| Zdroj: | Cancers Volume 12 Issue 8 Cancers, Vol 12, Iss 2161, p 2161 (2020) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12082161 |
| Popis: | 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&mdash 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. |
| Databáze: | OpenAIRE |
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