Taurolidine induces epithelial-mesenchymal transition via up-regulation of the transcription factor Snail in human pancreatic cancer cell lines
The taurine derivative taurolidine (TRD) exerts anti-neoplastic effects in a variety of tumor models. On the other hand, TRD at low doses was shown to reduce cell-cell adhesion, a prerequisite for metastasis. The aim of this study was to elucidate the effects of low-dose TRD on pancreatic cancer.
Human pancreatic cancer cell lines representing diverse states of differentiation were exposed to TRD for 24 h. Cell viability was assessed by MTT assay and trypan blue staining, apoptosis by caspase-3/7 activity, and flow-cytometric cell cycle analysis. Expression of Snail and E-cadherin was analyzed by polymerase chain reaction and Western blotting.
MTT-tested viability of all pancreatic cancer cell lines decreased dose-dependently up to 50 % of the untreated control. In contrast to staurosporine TRD (100 and 250 μM) did not induce apoptosis but increased the percentage of cells in G1/G0 arrest. Correlation of MTT test and trypan blue staining revealed a decreased adherence of vital tumor cells at 250 μM TRD. This was associated with reduced expression of the adhesion molecule E-cadherin and an increased expression of the transcription factor Snail, a regulator of epithelial-mesenchymal transition (EMT).
Low-dose TRD reduces not only viability but also cell-cell adherence and E-cadherin expression of pancreatic cancer cells, whereas the expression of the EMT inducer Snail was increased. By induction of these EMT hallmarks, low-dose TRD may promote metastasis in pancreatic cancer.
KeywordsPancreatic cancer Taurolidine EMT Snail Apoptosis
- 11.Braumann C, Winkler G, Rogalla P, Menenakos C, Jacobi CA (2006) Prevention of disease progression in a patient with a gastric cancer-re-recurrence. Outcome after intravenous treatment with the novel antineoplastic agent taurolidine. Report of a case. World J Surg Oncol 4:34PubMedCrossRefPubMedCentralGoogle Scholar
- 15.Neuzillet C, Sauvanet A, Hammel P (2011) Prognostic factors for resectable pancreatic adenocarcinoma. J Visc SurgGoogle Scholar
- 26.Braumann C, Gutt CN, Scheele J, Menenakos C, Willems W, Mueller JM, Jacobi CA (2009) Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial. World J Surg Oncol 7:32PubMedCrossRefPubMedCentralGoogle Scholar
- 27.Stendel R, Scheurer L, Schlatterer K, Stalder U, Pfirrmann RW, Fiss I, Mohler H, Bigler L (2007) Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients. Clin Pharmacokinet 46:513–524PubMedCrossRefGoogle Scholar
- 28.Imhof L, Goldinger SM, Baumann K, Schad K, French LE, Rothlisberger P, Dummer R (2010) The antibacterial substance, taurolidine in the second/third-line treatment of very advanced stage IV melanoma including brain metastases: results of a phase 2, open-label study. Melanoma ResGoogle Scholar
- 34.Chromik AM, Daigeler A, Bulut D, Flier A, May C, Harati K, Roschinsky J, Sulberg D, Ritter PR, Mittelkotter U, Hahn SA, Uhl W (2010) Comparative analysis of cell death induction by taurolidine in different malignant human cancer cell lines. J Exp Clin Cancer Res 29:21PubMedCrossRefPubMedCentralGoogle Scholar
- 36.Opitz I, van der Veen HC, Braumann C, Ablassmaier B, Fuhrer K, Jacobi CA (2003) The influence of adhesion prophylactic substances and taurolidine/heparin on local recurrence and intraperitoneal tumor growth after laparoscopic-assisted bowel resection of colon carcinoma in a rat model. Surg Endosc 17:1098–1104PubMedCrossRefGoogle Scholar
- 41.Arlt MJ, Walters DK, Banke IJ, Steinmann P, Puskas GJ, Bertz J, Rentsch KM, Ehrensperger F, Born W, Fuchs B (2011) The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity. Int J CancerGoogle Scholar