Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.
Anticancer Res
; 37(2): 437-444, 2017 02.
Article
en En
| MEDLINE
| ID: mdl-28179288
ABSTRACT
BACKGROUND:
Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. MATERIALS ANDMETHODS:
We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901.RESULTS:
B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition.CONCLUSION:
Polyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.Palabras clave
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Bases de datos:
MEDLINE
Asunto principal:
Sulfonas
/
Carbolinas
/
Inhibidores de Proteínas Quinasas
/
Proteína X Asociada a bcl-2
/
Proteína bcl-X
/
Aurora Quinasa B
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Anticancer Res
Año:
2017
Tipo del documento:
Article