Newly Published
Perioperative Medicine  |   August 2018
Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo
Author Notes
  • From the Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China (C.W., G.W.); Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom (C.W., T.D., H.Z., L.W., A.D., C.J., D.M.); Tianjin Research Institute of Anesthesiology, Tianjin, China (C.W., G.W.); Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin (R.D.S.); and Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (C.B.).
  • Submitted for publication November 1, 2017. Accepted for publication July 10, 2018.
    Submitted for publication November 1, 2017. Accepted for publication July 10, 2018.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Preliminary data of the current work were presented in the Winter Anesthetic Research Society Meeting: The Royal College of Anaesthetists, London, United Kingdom, October 1 to 2, 2014 (https://doi.org/10.1093/bja/aeu367).
    Preliminary data of the current work were presented in the Winter Anesthetic Research Society Meeting: The Royal College of Anaesthetists, London, United Kingdom, October 1 to 2, 2014 (https://doi.org/10.1093/bja/aeu367).×
  • C.W. and T.D. contributed equally to this article.
    C.W. and T.D. contributed equally to this article.×
  • Acknowledgments: The authors sincerely thank Prof. Zhongcong Xie, M.D, Ph.D. (Massachusetts General Hospital, Boston, Massachusetts), for his kind gift of the H4 cell line used in these studies.
    Acknowledgments: The authors sincerely thank Prof. Zhongcong Xie, M.D, Ph.D. (Massachusetts General Hospital, Boston, Massachusetts), for his kind gift of the H4 cell line used in these studies.×
  • Research Support: The project was supported by a grant from the British Oxygen Company Chair (to Prof. Ma), Royal College of Anaesthetists (London, United Kingdom); European Cooperation in Science and Technology Action (CA15204; Brussels, Belgium; to Prof. Ma); and grant 81600962 (to Dr. Chunyan Wang) from the National Natural Science Foundation (Beijing, China). Dr. Chunyan Wang also received a scholarship (2016041) from the China Scholarship Committee (Beijing, China). Tanweer Datoo received a president’s Ph.D. scholarship from Imperial College London (United Kingdom).
    Research Support: The project was supported by a grant from the British Oxygen Company Chair (to Prof. Ma), Royal College of Anaesthetists (London, United Kingdom); European Cooperation in Science and Technology Action (CA15204; Brussels, Belgium; to Prof. Ma); and grant 81600962 (to Dr. Chunyan Wang) from the National Natural Science Foundation (Beijing, China). Dr. Chunyan Wang also received a scholarship (2016041) from the China Scholarship Committee (Beijing, China). Tanweer Datoo received a president’s Ph.D. scholarship from Imperial College London (United Kingdom).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Prof. Ma: Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom. d.ma@imperial.ac.uk. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pharmacology / Respiratory System
Perioperative Medicine   |   August 2018
Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo
Anesthesiology Newly Published on August 28, 2018. doi:10.1097/ALN.0000000000002401
Anesthesiology Newly Published on August 28, 2018. doi:10.1097/ALN.0000000000002401
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Dexmedetomidine reduces cellular apoptosis, and it has been demonstrated previously that this antiapoptotic effect can not only increase cancer cell proliferation and migration but also reduce survival in experimental models of cancer growth.

  • Midazolam has proapoptotic effects and can reduce cancer cell survival. The mechanisms by which midazolam suppresses cancer cell progression remain to be defined.

What This Article Tells Us That Is New:

  • As expected, dexmedetomidine enhanced cancer cell proliferation and migration, primarily by the upregulation of antiapoptotic proteins. By contrast, midazolam suppressed cancer cell proliferation and migration, induced mitochondria mediated apoptosis, and enhanced free radical production. These anticancer effects of midazolam, mediated by its activity at the peripheral benzodiazepine receptor, were achieved at high concentrations only.

  • The data suggest that commonly used agents in the perioperative period may impact tumor cell growth; these effects have been demonstrated in preclinical studies, and therefore their relevance to clinical management of patients undergoing cancer surgery remains to be determined.

Background: Several factors within the perioperative period may influence postoperative metastatic spread. Dexmedetomidine and midazolam are widely used general anesthetics during surgery. The authors assessed their effects on human lung carcinoma (A549) and neuroglioma (H4) cell lines in vitro and in vivo.

Methods: Cell proliferation and migration were measured after dexmedetomidine (0.001 to 10 nM) or midazolam (0.01 to 400 μM) treatment. Expression of cell cycle and apoptosis markers were assessed by immunofluorescence. Mitochondrial membrane potential and reactive oxygen species were measured by JC-1 staining and flow cytometry. Antagonists atipamezole and flumazenil were used to study anesthetic mechanisms of action. Tumor burden after anesthetic treatment was investigated with a mouse xenograft model of lung carcinoma.

Results: Dexmedetomidine (1 nM) promoted cell proliferation (2.9-fold in A549 and 2-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), migration (2.2-fold in A549 and 1.9-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), and upregulated antiapoptotic proteins in vitro. In contrast, midazolam (400 μM) suppressed cancer cell migration (2.6-fold in A549 cells, P < 0.0001; n = 4), induced apoptosis via the intrinsic mitochondrial pathway, decreased mitochondrial membrane potential, and increased reactive oxygen species expression in vitro—effects partly attributable to peripheral benzodiazepine receptor activation. Furthermore, midazolam significantly reduced tumor burden in mice (1.7-fold vs. control; P < 0.05; n = 6 per group).

Conclusions: Midazolam possesses antitumorigenic properties partly mediated by the peripheral benzodiazepine receptor, whereas dexmedetomidine promotes cancer cell survival through signaling via the α2-adrenoceptor in lung carcinoma and neuroglioma cells.