title: Volatile anesthetics protect cancer cells against tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via caveolins.
abstract: BACKGROUND
  Volatile anesthetics have a dual effect on cell survival dependent on caveolin expression. The effect of volatile anesthetics on cancer cell survival and death after anesthetic exposure has not been well investigated. The authors examined the effects of isoflurane exposure on apoptosis and its regulation by caveolin-1 (Cav-1).
  
  
  METHODS
  The authors exposed human colon cancer cell lines to isoflurane and proapoptotic stimuli and assessed what role Cav-1 plays in cell protection. They evaluated apoptosis using assays for nucleosomal fragmentation, cleaved caspase 3 expression, and caspase activity assays. To test the mechanism, they used pharmacologic inhibitors (i.e., pertussis toxin) and assessed changes in glycolysis.
  
  
  RESULTS
  Apoptosis as measured by nucleosomal fragmentation was enhanced by isoflurane (1.2% in air) in HT29 (by 64% relative to control, P < 0.001) and decreased in HCT116 (by 23% relative to control, P < 0.001) cells. Knockdown of Cav-1 in HCT116 cells increased the sensitivity to apoptotic stimuli but not with scrambled small interfering RNA (siRNA) treatment (19.7 ± 0.4 vs. 20.0 ± 0.6, P = 0.7786 and 19.7 ± 0.5 vs. 16.3 ± 0.4, P = 0.0012, isoflurane vs. control in Cav-1 small interfering RNA vs. scrambled small interfering RNA treated cells, respectively). The protective effect of isoflurane with various exposure times on apoptosis was enhanced in HT29 cells overexpressing Cav-1 (P < 0.001 by two-way ANOVA). Pertussis toxin effectively blocked the antiapoptotic effect of isoflurane exhibited by Cav-1 in all cell lines. Cav-1 cells had increased glycolysis with isoflurane exposure; however, in the presence of tumor necrosis factor-related apoptosis-inducing ligand, this increase in glycolysis was maintained in HT29-Cav-1 but not control cells.
  
  
  CONCLUSIONS
  Brief isoflurane exposure leads to resistance against apoptosis via a Cav-1-dependent mechanism.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kawaraguchi
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007202:Indicators and Reagents; D010101:Oxygen Consumption / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018685:Anesthetics, Inhalation; D051242:Caveolin 1; D007202:Indicators and Reagents; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053148:Caspase 3; D019204:GTP-Binding Proteins