Abstract
BackgroundOsteosarcoma (OS) affects over 8000 dogs/year in the United States. The disease usually arises in the appendicular skeleton and metastasizes to the lung. Dogs with localized appendicular disease benefit from limb amputation and chemotherapy but most die within 6–12 months despite these treatments. Taurolidine, a derivative of taurine, has anti-tumor and anti-angiogenic effects against a variety of cancers. The following in vitro studies tested taurolidine as a candidate for adjuvant therapy for canine OS. Tests for p53 protein status and caspase activity were used to elucidate mechanisms of taurolidine-induced cell death.ResultsTaurolidine was cytotoxic to osteosarcoma cells and increased the toxicity of doxorubicin and carboplatin in vitro. Apoptosis was greatly induced in cells exposed to 125 μM taurolidine and less so in cells exposed to 250 μM taurolidine. Taurolidine cytotoxicity appeared caspase-dependent in one cell line; with apparent mutant p53 protein. This cell line was the most sensitive to single agent taurolidine treatment and had a taurolidine-dependent reduction in accumulated p53 protein suggesting taurolidine’s effects may depend on the functional status of p53 in canine OS.ConclusionTaurolidine’s cytotoxic effect appears dependent on cell specific factors which may be explained, in part, by the functional status of p53. Taurolidine initiates apoptosis in canine OS cells and this occurs to a greater extent at lower concentrations. Mechanisms of cell death induced by higher concentrations were not elucidated here. Taurolidine combined with doxorubicin or carboplatin can increase the toxicity of these chemotherapy drugs and warrants further investigation in dogs with osteosarcoma.
Highlights
Osteosarcoma (OS) affects over 8000 dogs/year in the United States
It can be seen that 20 μM taurolidine enhanced the effect of doxorubicin but the best that could be expected under these conditions would be, on average, zero growth
Adding 20 μM taurolidine to carboplatin enhanced the effect of carboplatin alone but only in the D17 cell line
Summary
Osteosarcoma (OS) affects over 8000 dogs/year in the United States. The disease usually arises in the appendicular skeleton and metastasizes to the lung. Taurolidine, a derivative of taurine, has anti-tumor and anti-angiogenic effects against a variety of cancers. An increased understanding of the pathogenesis of OS is needed in order to facilitate the development of more effective therapeutic strategies One such strategy is to Taurolidine is a derivative of the amino acid taurine that has anti-tumor and anti-angiogenic effects against a variety of cancers [4,5,6]. Developed for its antibacterial properties, taurolidine has few detrimental effects on normal cells [7] but inhibits cancer cell proliferation [8] and tumor growth by inducing apoptosis [5,9,10,11,12] possibly through p53-dependent mechanisms [13].
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