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


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Abstract

Editor’s PerspectiveWhat We Already Know about This TopicDexmedetomidine 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 NewAs 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.

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