title: Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination.
abstract: BACKGROUND
  Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported that general anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This has important clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate the effect of anaesthetics isoflurane and propofol on prostate cancer malignancy.
  
  
  METHODS
  Prostate cancer (PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potential was assessed through evaluation of expression level of hypoxia-inducible factor-1α (HIF-1α) and its downstream effectors, cell proliferation and migration as well as development of chemoresistance.
  
  
  RESULTS
  We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1α and its downstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, with an increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1α neosynthesis through upper pathway blocking by a PI-3K-Akt inhibitor or HIF-1α siRNA abolished isoflurane-induced effects. In contrast, the intravenous anaesthetic propofol inhibited HIF-1α activation induced by hypoxia or CoCl2. Propofol also prevented isoflurane-induced HIF-1α activation, and partially reduced cancer cell malignant activities.
  
  
  CONCLUSIONS
  Our findings suggest that modulation of HIF-1α activity by anaesthetics may affect cancer recurrence following surgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancer surgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimen for cancer patients.
authors: 1] Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK [2] Department of Anesthesiology, West China Second Hospital, Sichuan University, Chengdu, China.
authors: H
authors: H
authors: Huang
authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors: L L
authors: LL
authors: Benzonana
authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors: H
authors: H
authors: Zhao
authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors: H R
authors: HR
authors: Watts
authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors: N J S
authors: NJ
authors: Perry
authors: Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
authors: C
authors: C
authors: Bevan
authors: Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
authors: R
authors: R
authors: Brown
authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors: D
authors: D
authors: Ma
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D015742:Propofol / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043823:Taxoids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D007530:Isoflurane; D015742:Propofol