BACKGROUND: To improve radioiodine treatment of metastasized differentiated thyroid carcinomas, substances that increase iodide uptake are needed. Many tumors are not responsive to retinoic acid as a differentiating agent. Therefore, identification of other differentiating substances is needed. Arsenic trioxide (ATO) was investigated for its potential to increase iodide uptake. METHODS: The action of ATO on proliferation, differentiation, and apoptosis was evaluated in follicular and papillary thyroid carcinoma cell lines. To get insight into the mode of action of ATO, coincubations with inhibitors of the phosphoinositide 3 (PI3) kinase pathway (V-Akt Murine Thymoma Viral Oncogene Homolog 1, Akt inhibitors) were performed; glutathione (GSH) levels were determined, as well as synergistic effects of ATO with inhibitors of GSH metabolism, inductors of oxidative stress. As a potential additional target of the pleiotropic action of ATO, its effect on glucose uptake was investigated. The expression of sodium iodide symporter, pendrin, phospho-Akt, and glucose transporter 1 was studied to reveal a potential effect of ATO on the transcription of specific genes. RESULTS: ATO reduced proliferation, increased iodide uptake and apoptosis, and, as an additional new mechanism, decreased glucose uptake in transformed thyrocytes. The pharmacological reduction of the amount of reduced GSH was effective in enhancing the differentiating action of ATO, whereas the combination of ATO with Akt-1 inhibitors reduced cell number but did not increase differentiation. CONCLUSIONS: Our study suggests a new therapeutic option for postoperative treatment of radioiodine nonresponsive differentiated thyroid carcinomas.
BACKGROUND: To improve radioiodine treatment of metastasized differentiated thyroid carcinomas, substances that increase iodide uptake are needed. Many tumors are not responsive to retinoic acid as a differentiating agent. Therefore, identification of other differentiating substances is needed. Arsenic trioxide (ATO) was investigated for its potential to increase iodide uptake. METHODS: The action of ATO on proliferation, differentiation, and apoptosis was evaluated in follicular and papillary thyroid carcinoma cell lines. To get insight into the mode of action of ATO, coincubations with inhibitors of the phosphoinositide 3 (PI3) kinase pathway (V-Akt Murine Thymoma Viral Oncogene Homolog 1, Akt inhibitors) were performed; glutathione (GSH) levels were determined, as well as synergistic effects of ATO with inhibitors of GSH metabolism, inductors of oxidative stress. As a potential additional target of the pleiotropic action of ATO, its effect on glucose uptake was investigated. The expression of sodium iodide symporter, pendrin, phospho-Akt, and glucose transporter 1 was studied to reveal a potential effect of ATO on the transcription of specific genes. RESULTS:ATO reduced proliferation, increased iodide uptake and apoptosis, and, as an additional new mechanism, decreased glucose uptake in transformed thyrocytes. The pharmacological reduction of the amount of reduced GSH was effective in enhancing the differentiating action of ATO, whereas the combination of ATO with Akt-1 inhibitors reduced cell number but did not increase differentiation. CONCLUSIONS: Our study suggests a new therapeutic option for postoperative treatment of radioiodine nonresponsive differentiated thyroid carcinomas.