Anaesthetics influence leukaemia cell biology and malignancy: Mechanisms and Implications

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common type of cancer in children. During ALL treatments, general anaesthetics are often used on patients undergoing painful procedures. General anaesthetics have been shown to influence cancer cell biology in solid cancer models. However, no study has been published regarding the effects of anaesthetics on leukaemia. To further our understanding, the objective of this thesis is to compare the effects of two commonly used general anaesthetics (intravenous: propofol and inhalational: sevoflurane) on ALL in vitro and in vivo.

Propofol and sevoflurane reduce proliferation, CXCR4 expression, osteopontin (OPN) secretion and migration of leukaemia cells in vitro. In addition, both anaesthetics reduce homing and migration of leukaemia cells in vivo. Upon further investigation, hypoxia-inducible factor-1 alpha (HIF-1α) is responsible for induced molecular changes in leukaemia cells. HIF-1α is reduced by propofol in a dose-dependent manner, and its effect is relatively short-term (<24 hours). On the other hand, HIF-1α is inhibited by sevoflurane in a time-dependent manner with more sustainable effects lasting more than 24 hours. The reduction of HIF-1α expression by propofol is likely due to the inhibition of the phosphorylation of ERK and AKT. Sevoflurane only decreases the phosphorylation of ERK. Chemoresistance study reveals both propofol and sevoflurane enhance the cytotoxic effect of the chemotherapeutic agent (Ara-C). Both anaesthetics are shown to potentiate caspase-based apoptotic pathways when given together with Ara-C to leukaemia cells.

In addition to HIF-1α, OPN is shown to regulate anaesthetic induced molecular changes in leukaemia cells in vitro. Upon further investigation, OPN forms an auto feedback loop with HIF-1α in leukaemia cells, regulating CXCR4 expression, migration and chemoresistance of leukaemia cells in vitro. In summary, our data demonstrate both propofol and sevoflurane may potentially reduce the malignancy of ALL.