Propofol inhibits biological functions of leukaemia stem and differentiated cells through suppressing Wnt/β-catenin and Akt/mTOR

The biological roles of intravenous anaesthetic propofol in cancer have been shown by various studies using cancer cell lines that represent differentiated cancer cells. However, the activities of propofol in cancer stem cells have not been elucidated. In this work, we examined the effects and mechanisms of propofol on acute myeloid leukaemia (AML) differentiated and CD34(+)CD38(-) stem cells. We found that propofol inhibited growth, differentiation and self-renewal capabilities of AML stem cells regardless of cellular origin and genetic profiling. In addition, propofol inhibited the growth of AML differentiated cells. Propofol significantly induced apoptosis of AML differentiated but not CD34(+)CD38(-) stem cells. We further found that propofol significantly augmented the efficacy of AML standard therapeutic drugs. Consistent with the previous findings, we showed that propofol suppressed the Akt/mTOR pathway in AML cells. We also found that propofol inhibited pathways important for stem cell maintenance and self-renewal, such as Wnt/beta-catenin. Overexpression of constitutively active Akt partially reversed the inhibitory effects of propofol in AML differentiated cells. Stabilization of beta-catenin using genetic and pharmacological approaches also partially rescued the inhibitory effects of propofol in AML differentiated and stem cells. Our work shows that propofol targets leukaemia cells at all stages of development, in a cell type-specific manner. Inhibition of both Akt/mTOR and Wnt/beta-catenin is required for the action of propofol in AML. Our findings also highlight the activities of propofol on cancer stem cells.