Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

作者：Wang, Chunyan; Datoo, Tanweer; Zhao, Hailin; Wu, Lingzhi; Date, Akshay; Jiang, Cui; Sanders, Robert D.; Wang, Guolin; Bevan, Charlotte; Ma, Daqing^*

来源：Anesthesiology, 2018, 129(5): 1000-1014.

DOI：10.1097/ALN.0000000000002401

• BREAST-CANCER CELLS
• MITOCHONDRIAL PERMEABILITY TRANSITION
• PERIPHERAL BENZODIAZEPINE-RECEPTORS
• TUMOR-GROWTH
• APOPTOSIS
• MICE
• PROLIFERATION
• PATHWAY
• ANESTHESIA
• ISOFLURANE

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 10nM) or midazolam (0.01 to 400 M) 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 (1nM) 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 M) 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 vitroeffects 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 (2)-adrenoceptor in lung carcinoma and neuroglioma cells.

• 出版日期2018-11
• 单位天津医科大学