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Drug targeting the actin cytoskeleton potentiates the cytotoxicity of low dose vincristine by abrogating actin-mediated repair of spindle defectsстатья
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 8 сентября 2020 г.
- Авторы: Yao Wang, Stear Jeffrey H., Ashleigh Swain, Xing Xu, Bryce Nicole S., Michael Carnell, Alieva Irina B., Dugina Vera B., Cripe Timothy P., Justine Stehn, Hardeman Edna C., Gunning Peter W.
- Журнал: Molecular Cancer Research
- Том: 18
- Номер: 7
- Год издания: 2020
- Издательство: American Association for Cancer Research
- Местоположение издательства: United States
- Первая страница: 1074
- Последняя страница: 1087
- Номер статьи: Print ISSN 1541-7786
- DOI: 10.1158/1541-7786.MCR-19-1122
- Аннотация: Anti-microtubule vinca alkaloids are widely used in the clinic but their toxicity is often dose-limiting. Strategies that enhance their effectiveness at lower doses are needed. We show that combining vinca alkaloids with compounds that target a specific population of actin filaments containing the cancer-associated tropomyosin Tpm3.1 result in synergy against a broad range of tumor cell types. We discovered that low concentrations of vincristine alone induce supernumerary microtubule asters that form transient multi-polar spindles in early mitosis. Over time these asters can be reconstructed into functional bipolar spindles resulting in cell division and survival. These microtubule asters are organized by the nuclear mitotic apparatus protein (NuMA)-dynein-dynactin complex without involvement of centrosomes. However, anti-Tpm3.1 compounds at non-toxic concentrations inhibit this rescue mechanism resulting in delayed onset of anaphase, formation of multi-polar spindles and apoptosis during mitosis. These findings indicate that drug targeting actin filaments containing Tpm3.1 potentiates the anti-cancer activity of low dose vincristine treatment. Implications: Simultaneously inhibiting Tpm3.1-containing actin filaments and microtubules is a promising strategy to potentiate the anti-cancer activity of low dose vincristine.
- Добавил в систему: Алиева Ирина Борисовна