Anaesthetics affect cancer cell biology through cellular signalling and metabolic modulations

Abstract

Surgery remains the first-line treatment for most cancer types. However, anaesthetic use during surgery may influence cancer cell biology and hence affect cancer recurrence. The current PhD study project objective is to evaluate the effects of two general anaesthetics, sevoflurane (inhalational) and propofol (intravenous), on cancer cells. This study intends to understand the impact of anaesthetics on cancer recurrence following surgery and ultimately provide the research rationale of clinical study/trials for improving cancer surgical outcomes. Propofol inhibited lung, colonic, renal, and ovarian cancer cell malignancy in a dose- dependent manner through regulating PEDF* and HIF-1α expressions. Propofol also altered the metabolites of lung, colonic, renal, and ovarian cancer cells that inhibited the lung and ovarian cancer cell glucose metabolism. It was demonstrated that propofol inhibited lung cancer cell malignancy through downregulating GLUT1 and MPC1, thus disturbing glucose metabolism. These processes induced the high PEDF expression, which downregulated HIF-1α via the Akt pathways, thus regulated pro- and anti-tumour genes. However, propofol neither inhibited brain cancer cell malignancy nor affected the above molecular entities. In contrast, sevoflurane enhanced colonic, renal and ovarian cancer cell malignancy through upregulating VEGFA. Sevoflurane upregulated GLUT1, MPC1 and GLUD1, which enhanced ovarian cancer cellular glucose metabolism. These changes inhibited PEDF expression, and its reduction resulted in upregulating HIF-1α via the Erk pathway, which upregulated two pro-tumour gene-encoded proteins, namely CXCL12 and CXCR4. However, propofol had the opposite effect on these cellular signalling and metabolic pathways in ovarian cancer cells. In summary, this PhD project demonstrated that sevoflurane may have pro-tumour while propofol might have anti-cancer properties. According to laboratory evidence found in the current study, propofol, unlike sevoflurane, may benefit cancer surgery patients. The work presented in this thesis may provide a foundation for further clinical studies to optimise the anaesthesia regimen for better surgical outcomes following cancer surgery.