Mechanistic and antineoplastic evaluation of taurolidine in the DU145 model of human prostate cancer.
Taurolidine (TRD) was designed in the 1970s as a broad-spectrum antibiotic and is used clinically at high doses without systemic toxicity. We have found that this agent possesses cytotoxic activity in human tumor cell lines and antineoplastic activity in mice bearing i.p. human tumor xenografts. We now report the mechanism by which TRD induces cell death in DU145 human prostate tumor cells. The IC50 (3 days) of TRD in this model was 16.8+/-1.1 microM. Cytotoxicity was associated with DNA debris and increased membrane phosphatidylserine externalization, both suggesting the induction of apoptosis. This was confirmed by the ability of TRD to induce PARP cleavage in these cells, an effect prevented by coexposure to the pan-caspase inhibitor zVAD-FMK. TRD exposure also resulted in the appearance of cytochrome c in the cytoplasm, procaspase 9 activation within 2 h of drug exposure and procaspase 8 activation 4 h after exposure. Parallel experiments revealed that cytochrome c appearance in the cytoplasm was not blocked by preexposure to zVAD-FMK, while activation of both procaspase 9 and procaspase 8 was prevented. Finally, antineoplastic activity was assessed in mice bearing subcutaneous xenografts of DU145 cells. Initial studies quantitated the toxicity of three i.p. injections of TRD, administered as one injection on three alternate days per week, at doses ranging from 500 to 700 mg/kg per injection. The 500 mg/kg dose produced about 7% mortality after three cycles and effectively inhibited tumor growth. Thus, TRD induced mitochondrial-mediated apoptosis in DU145 human prostate tumor cells and this effect could be exploited for therapeutic advantage.
Darnowski
James W
JW
Department of Medicine, Divisions of Clinical Pharmacology and Medical Oncology, Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. jdarnowski@lifespan.org
Goulette
Frederick A
FA
Cousens
Leslie P
LP
Chatterjee
Devasis
D
Calabresi
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009374:Neoplasms, Experimental; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D013654:Taurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013829:Thiadiazines / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D013829:Thiadiazines; D013654:Taurine; C012566:taurolidine