Taurolidine and oxidative stress: a rationale for local treatment of mesothelioma.
Malignant mesothelioma is an asbestos-related, aggressive tumour, resistant to most anticancer therapies. Akt is a key mediator of mesothelioma cell survival and chemoresistance. This study aimed to clarify the mechanism by which taurolidine (TN), a known synthetic compound with antimicrobial and antineoplastic properties, leads to mesothelioma cell death. Apoptosis was studied by annexin V binding, cell cycle analysis, caspase-8 activation, poly(ADP-ribose) polymerase (PARP) cleavage and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL). Oxidative stress was measured by nitrite production and DNA oxidative damage. Protein expression and phosphorylation were evaluated by immunoprecipitation and immunoblotting. TN induces cell death of mesothelioma cells, but not of non-neoplastic human mesothelial cells. After TN treatment of mesothelioma cells, Akt but not extracellular signal-regulated kinase (Erk) 1/2 activity is inhibited a in time- and dose-dependent manner. Protein phosphatase (PP)1alpha and PP2A are activated several hours after drug addition. Apoptosis induced by TN is driven by oxidative stress and cell exposure to sulfydryl donors, such as glutathione monoethylester and l-N-acetylcysteine, significantly reduced pro-apoptotic effects and Akt inhibition. Conversely, expression of constitutively activated Akt did not affect cytoxicity elicited by TN, which retained its ability to inhibit the kinase. TN induces mesothelioma cell death via oxidative stress, accompanied by inhibition of Akt signalling. This provides a promising molecular rationale for TN as local treatment of malignant mesothelioma.
Aceto
N
N
DISCAFF Dept and DFB Center, University of Piemonte Orientale A. Avogadro, Novara, Italy.
Bertino
P
P
Barbone
D
D
Tassi
G
G
Manzo
L
L
Porta
C
C
Mutti
L
L
Gaudino
G
G
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013829:Thiadiazines / Q000627:therapeutic use*; D013997:Time Factors
D000970:Antineoplastic Agents; D013829:Thiadiazines; D013654:Taurine; C012566:taurolidine; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt