Taurolidine induces apoptosis of murine melanoma cells in vitro and in vivo by modulation of the Bcl-2 family proteins.
BACKGROUND
This study evaluates whether taurolidine, a novel antibiotic agent, induces murine melanoma cell apoptosis in vitro and in vivo.


METHODS
Murine melanoma cells (B16 4A5 and B16 F10) were treated with taurolidine (0-100 microM) for 12 and 24 hr. Cell viability and apoptosis were assessed by MTT assay and FACScan analysis. Expression of the Bcl-2 family proteins was detected by Western blot analysis. In vivo, taurolidine-induced anti-tumor cytotoxicity was assessed in C57BL/6 mice. Therapeutic effectiveness, by intraperitoneal injection of taurolidine (15 mg/mouse) on alternate days for 2 weeks, was evaluated in mice bearing B16 4A5 tumor xenografts. Primary and metastatic tumor growth and intra-tumor apoptotic index were measured.


RESULTS
Taurolidine induced cell apoptosis and reduced cell viability in murine melanoma cells. The pro-apoptotic protein Bax was enhanced, whereas the anti-apoptotic protein Bcl-2 was inhibited by taurolidine treatment. In vivo, systemic injection of 15-mg taurolidine was identified as the maximally tolerated dose. Administration of taurolidine at 15 mg/mouse significantly inhibited primary and metastatic tumor growth, which was mirrored by a significantly increased intra-tumor apoptotic index.


CONCLUSIONS
These results demonstrate that taurolidine significantly attenuated melanoma tumor growth, which may result from taurolidine-induced apoptosis by modulation of the Bcl-2 family proteins.
Sun
Bao Sheng
BS
Deparment of Academic Surgery, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland.
Wang
Jiang Huai
JH
Liu
Lin Lin
LL
Gong
Shou Liang
SL
Redmond
H Paul
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000473:pathology*; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000187:drug effects
D000970:Antineoplastic Agents; C494826:BAX protein, human; D013829:Thiadiazines; D051028:bcl-2-Associated X Protein; D013654:Taurine; C012566:taurolidine