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Abstract
Background
Although so many experimental trials have been done to improve the redifferentiation and responsiveness of radioiodide therapy, they have not yet yielded any satisfactory results. As statins inhibit both farnesylation and geranylgeranylation, they have been reported to have an antineoplastic and redifferentiation effect in experimental and clinical studies. In this study, we investigated the relationship between statins and the alteration of the NIS expression and, TPC-1 cell apotosis to evaluate the possibility of using statins as adjuvant therapeutic agents for papillary thyroid cancer.
Methods
We used the TPC-1 cell lines for our experiments. Cell viabilities were measured by CCK-8. The degrees of apoptosis and, the expressions of NIS mRNA and NIS protein were measured by flow cytometry, semi quantitative RT-PCR and Western blot assay.
Results
Increased levels of NIS mRNA and NIS protein were observed under therapeutic blood concentrations (concentrations of simvastatin: 20, 50, 80 nM, concentrations of atorvastatin: 50, 80,110 nM), but the dose-response relationship was only manifested within simvastatin. The TPC-1 cells showed a concentration dependent decrease of viability and an increase of apoptosis not under therapeutic blood concentrations, but under excessively high concentrations (after treatment with 10-50 µM of atorvastatin and with 1-10 µM of simvastatin).
Conclusion
The results of this study show that effective therapeutic blood concentrations of simvastatin and atorvastatin can give a favorable effect on the NIS expression under effective therapeutic blood concentrations. Therefore, we demonstrated the possibility that simvastatin and atorvastatin might have an important role as adjuvant therapeutic agents to improve the responsiveness of radioiodide therapy for papillary thyroid cancer. Further studies are needed to clarify this issue.
Figures and Tables
Fig. 1
Human NIS mRNA expression after treatment of simvastatin and atorvastatin. A. After treatment of each statins for 48 hr, human NIS mRNA expression treated with simvastatin was detected in a dose dependent manner by semiquantitative RT-PCR. But, human NIS mRNA expression treated with atorvastatin showed the only increase of mRNA expression in a dose independent manner. Treated concentrations of statins were decided by the range of effective blood concentrations which normal healthy adults ingest simvastatin or atorvastain 40 mg P.O. (C: control). B. These graphs show the increased percent of relative mRNA expression in a dose dependent manner after treatment of simvastatin. But, atorvastain showed the only increased percent of relative mRNA expression in a dose independent manner. These densitometric result were measured by Multi Gauge 3.0. (concentrations of simvastatin: 20, 50, 80 nM, atorvastatin: 50, 80,110 nM).
Fig. 2
Human NIS protein expression after treatment of simvastatin and atorvastatin. A. After treatment of each statins for 48 hr, human NIS protein expression treated with simvastatin was detected in a dose dependent manner by Western blot. But, human NIS protein expression treated with atorvastatin showed the only increase of protein expression in a dose independent manner. Treated concentrations of statins were decided by the range of effective blood concentrations which normal healthy adults ingest simvastatin or atorvastain 40 mg P.O. (C: control). B. These graphs show the increased percent of relative protein expression in a dose dependent manner after treatment of simvastatin. But, atorvastain showed the only increased percent of relative protein expression in a dose independent manner. These densitometric result were measured by Multi Gauge 3.0. (concentrations of simvastatin: 20, 50, 80 nM, atorvastatin: 50, 80,110 nM).
Fig. 3
Viability of TPC-1 cell and depending on both simvastatin and atorvastatin concentrations. TPC-1 cell were exposed to the indicated concentrations of simvastatin (1-10 µM) or atorvastatin (10-50 µM) for 48 hr, and cell viability was measured by CCK-8 assay. Cell viability decreased in a dose dependent manner. A. Simvastatin, B. Atorvastatin (data shown are mean ± SD) (P < 0.05).
Fig. 4
Induction of apoptosis in TPC-1 cell treated with simvastatin and atorvastatin. A. After treatment of simvastatin and atorvastatin for 48 hr, TPC-1 cells were double stained with Annexin V and PI staining for 15 min and followed by FACS analysis. Induction of apoptosis in TPC-1 cell treated with each agent was increased by concentration. B. These graphs show the increase of apoptosis in a dose dependent manner. (C: control, S1: Simvastatin 1 µM, S5: Simvastatin 5 µM, S10: Simvastatin 10 µM, A10: Atorvastatin 10 µM, A20: Atorvastatin 20 µM, A30: Atorvastatin 30 µM).
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