TY - JOUR
T1 - Taurolidine and oxidative stress
T2 - A rationale for local treatment of mesothelioma
AU - Aceto, N.
AU - Bertino, P.
AU - Barbone, D.
AU - Tassi, G.
AU - Manzo, L.
AU - Porta, C.
AU - Mutti, L.
AU - Gaudino, G.
PY - 2009/12
Y1 - 2009/12
N2 - 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 transferasemediated 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)1a 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. Copyright
AB - 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 transferasemediated 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)1a 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. Copyright
KW - Akt
KW - Apoptosis
KW - Malignant mesothelioma
KW - Oxidative stress
KW - Taurolidine
UR - http://www.scopus.com/inward/record.url?scp=73249125863&partnerID=8YFLogxK
U2 - 10.1183/09031936.00102308
DO - 10.1183/09031936.00102308
M3 - Article
SN - 0903-1936
VL - 34
SP - 1399
EP - 1407
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 6
ER -