Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma.
Taurolidine and povidone-iodine (PVP-I) are used in every day clinical practice, taurolidine as a broad spectrum antibiotic, and PVP-I as an antiseptic. The type of cell death induced in malignant pleural mesothelioma (MPM) cell lines by these agents was compared, and their ability to sensitize to chemotherapy assessed. Both taurolidine and PVP-I inhibited MPM cell growth after 7.5min incubation, but taurolidine was more effective at later time points and was more specific towards tumour cells than PVP-I. Taurolidine induced death by caspase-dependent and independent mechanisms, whereas in contrast, PVP-I induced a necrotic phenotype that was not caspase-dependent. Interestingly, both taurolidine and PVP-I induced the production of reactive oxygen intermediates and decreased mitochondrial membrane permeability, and cell death was inhibited by the oxygen scavenger N-acetyl cysteine. Taurolidine but not PVP-I treatment resulted in p53 activation in 2/3 MPM cell lines and a decrease in the protein levels of survivin, Bcl-2 and Mcl-1. Survivin also decreased in response to PVP-I whereas Bcl-xL remained unaffected by both treatments. Targeting of Bcl-xL with siRNA sensitized MPM cells to taurolidine and taurolidine treatment sensitized MPM cells to cisplatin-induced apoptosis. In conclusion, taurolidine and PVP-I are both cytotoxic to human MPM cells at early and late time points and induce reactive oxygen intermediate production. Taurolidine induces apoptosis and necrosis, activates p53 and sensitizes cells to cisplatin, whereas PVP-I inhibits cell growth via necrosis. Both agents are promising candidates for use in local treatment within multimodality concepts for MPM.
Opitz
I
I
Division of Thoracic Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
Sigrist
B
B
Hillinger
S
S
Lardinois
D
D
Stahel
R
R
Weder
W
W
Hopkins-Donaldson
S
S
D000891:Anti-Infective Agents, Local; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001706:Biopsy; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011206:Povidone-Iodine / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013829:Thiadiazines / Q000627:therapeutic use*
D000891:Anti-Infective Agents, Local; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013829:Thiadiazines; D013654:Taurine; D011206:Povidone-Iodine; C012566:taurolidine; D053148:Caspase 3; D002945:Cisplatin