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치료 불응성 갑상선암에 대한 실험적 치료 약제: Histone Deacetylase Inhibitor, PPAR-gamma Agonist, Retinoic Acid
정웅윤,OrloHClark<SUP>1<,SUP>,Woung Youn Chung and Orlo H Clark,<SUP>1<,SUP> 대한갑상선-내분비외과학회 2005 The Koreran journal of Endocrine Surgery Vol.5 No.2
Most patients with thyroid cancer have well differentiated tumors that usually respond to conventional therapy including total or near total thyroidectomy, radioiodine ablation and TSH suppression. About 10% of patients, however, have aggressive cancers as a consequence of de-differentiation. During de-differentiation, thyroid cancers not only show more mitosis, fibrosis, and altered cell structure, they also lose thyroid-specific functions (iodine uptake, TSH receptor expression, and thyroglobulin production). These poorly differentiated or undifferentiated tumors mostly fail to take up radioiodine and are responsible for most deaths from thyroid cancer. New therapies need to be developed for patients with these types of tumors. Among the most promising antineoplastic therapies for these poorly differentiated and undifferentiated thyroid cancers are the histone deacetylase inhibitors, the PPAR-gamma agonist and retinoic acids. These drugs have therapeutic effects for thyroid cancers in inhibiting growth and inducing apoptosis and redifferentiation, in vivo and in vitro studies. And, clinical trials in patients with refractory thyroid cancers have been initiated. Further laboratory investigation of these drugs is necessary to understand molecular mechanisms and demonstrate therapeutic efficacy for thyroid cancers. (Korean J Endocrine Surg 2005;5:69-74)
갑상선암 세포주에서 Troglitazone에 의한 TRAIL-유도 세포소멸 감수성의 증가
박진우,OrloH.Clark<SUP>1<.SUP>.Jin-Woo Park and Orlo H. Clark<SUP>1<.SUP> 대한갑상선-내분비외과학회 2003 The Koreran journal of Endocrine Surgery Vol.3 No.2
Purpose: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis in many human cancer cells but not in normal cells. Thyroid cancer cells, however, appear to be relatively resistant to TRAIL-induced apoptosis. We investigated the effect of troglitazone, a PPARγ agonist, on TRAIL-induced apoptosis in thyroid cancer cells. Methods: We used 6 thyroid cancer cell lines: TPC-1, FTC- 133, FTC-236, FTC-238, XTC-1, and ARO82-1. We used flow cytometry to detect apoptosis and used MTT assay to measure anti-proliferation effects. ANOVA was used for statistical analysis. Results: TPC-1 cells were the most sensitive to soluble TRAIL. FTC-133 and ARO82-1 were resistant to TRAIL and growth inhibition was less than 20% at concentration of 800 ng/ml of TRAIL. In both TPC-1 (TRAIL-sensitive) and FTC- 133 (TRAIL-resistant) thyroid cancer cell lines, pretreatment with troglitazone enhanced TRAIL-induced cell death significantly. Bcl-family proteins did not seem to be involved in sensitization of TRAIL-induced apoptosis by troglitazone. Conclusion: TRAIL in combination with troglitazone induces apoptosis in thyroid cancer cells at suboptimal concentrations that can not be achieved using TRAIL alone. (Korean J Endocrine Surg 2003;3:113-120)
갑상선암 세포주에서 Na-4-Phenylbutyrate의 세포 증식 억제 및 분화 유도 효과
최영진(Young Jin Choi),박진우(Jin-Woo Park),장이찬(Lee-Chan Jang),최재운(Jae-Woon Choi),Orlo H. Clark 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.75 No.3
Purpose: Sodium-4-phenylbutyrate (Na-4-PB) is an analogue of phenylacetate, which is a well-known redifferentiating agent. In vitro and in vivo studies on this agent have been done and the clinical relevance of Na-4-PB has been studied in other malignancies, but not in thyroid cancer. We investigated the effect of Na-4-PB on cell proliferation and differentiation in thyroid cancer cell lines. Methods: We used 5 thyroid cancer cell lines: TPC-1, FTC-133, FTC-236, FTC-238 and XTC-1. MTT assay and flowcytometry were used to measure the agent’s antiproliferative effects and the cell cycle change. We evaluated the PPARγ expression via western blotting and the mRNA expressions of NIS, Tg and CD 97 were determined by performing RT-PCR. Troglitazone, a potent PPARγ agonist, was used in combined treatment with Na-4-PB. Results: Na-4-PB inhibited cell proliferation in a dose and time dependent manner in all 5 thyroid cancer cell lines. By performing flowcytometry in the FTC-133 and TPC-1 cell lines, we identified that the antiproliferative effect of Na-4-PB was associated with an increased apoptotic cell population. Treatment with Na-4-PB upregulated the PPARγ expression, but the combined treatment of Na-4-PB with troglitazone did not seem to be synergistic for the antiproliferative effect. Treatment with Na-4-PB downregulated the CD97 mRNA expression and it upregulated the NIS and Tg mRNA expressions in both the FTC-133 and TPC-1 cell lines. Conclusion: Na-4-PB inhibited thyroid cancer cell proliferation by inducing apoptosis in a dose dependent manner. Treatment with Na-4-PB increased the expression of PPARγ and it upregulated such differentiation markers as NIS and Tg, and it downregulated CD97, a dedifferentiation marker. Na-4-PB should be further evaluated as a new potential therapeutic agent for patients with thyroid cancer.