Partner: Stanisław Pikul |
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Ostatnie publikacje
1. | Zdioruk M.♦, Want A.♦, Mietelska-Porowska A.♦, Laskowska-Kaszub K.♦, Wojsiat J.♦, Klejman A.♦, Użarowska E.♦, Koza P.♦, Olejniczak S.♦, Pikul S.♦, Konopka W.♦, Golab J.♦, Wojda U.♦, A new inhibitor of tubulin polymerization kills multiple cancer cell types and reveals p21-mediated mechanism determining cell death after mitotic catastrophe, Cancers, ISSN: 2072-6694, DOI: 10.3390/cancers12082161, Vol.12, No.8, pp.2161-1-21, 2020 Streszczenie: 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. Słowa kluczowe: cancer, chemotherapeutic, microtubule-poison, vincristine, mitotic catastrophe, non-apoptotic cell death, p21, p53 Afiliacje autorów:
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