Volatile anesthetics sevoflurane targets leukemia stem/progenitor cells via Wnt/β-catenin inhibition - 20/09/18
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Graphical abstract |
Highlights |
• | Sevoflurane inhibits growth but not survival of CML differentiated cells. |
• | Sevoflurane inhibits CML stem cell differentiation and self-renewal but not survival. |
• | Sevoflurane inhibits normal stem cells in a less extent than leukemia stem cells. |
• | Sevoflurane acts on CML via Wnt/β-catenin inhibition. |
Abstract |
Most of the studies regarding the direct effect of anesthetics on tumour cells are focused on opioids and voltage-gated sodium channels. Little is known on the effect of volatile anesthetics on tumour progression. In this study, we show that sevoflurane, a volatile anesthetic, negatively affects chronic myeloid leukemia (CML) CD34 stem/progenitor cells’ biological properties. Sevoflurane significantly inhibits the growth of a panel of CML cell lines in a dose-dependent manner without affecting their survival. It also inhibits proliferation, differentiation and self-renewal capacities but not survival of CML CD34 cells. In addition, sevoflurane significantly augments dasatinib’s efficacy in CML cell lines and stem/progenitors. Mechanistically, sevoflurane dose-dependently decreases levels of β-catenin and c-Myc but not phospho-P38 MAPK in K562 and CML CD34 cells. The decreased Wnt/ β-catenin activity and the reduced levels of Wnt/β-catenin-targeted transcriptions are observed in CML cells exposed to sevoflurane. The complete rescue of the inhibitory effects of sevoflurane in K562 and CML CD34 cells by β-catenin stabilization using both genetic and pharmacological approaches further demonstrates that sevoflurane acts on CML cells via a β-catenin-dependent manner. Our results clearly show the direct and negative effects of sevoflurane on the leukemia cell lines as well as leukemia stem/progenitors. Our findings also reveal Wnt/β-catenin as the target of volatile anesthetics.
El texto completo de este artículo está disponible en PDF.Keywords : Sevoflurane, Volatile anesthetics, Wnt/β-catenin, Stem/progenitors, Leukemia
Esquema
Vol 107
P. 1294-1301 - novembre 2018 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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