ABSTRACT
ObjectiveTo study the changes of iodine uptake of the follicular thyroid carcinoma cell line (FTC-133) and nude mice bearing human follicular thyroid carcinoma after the induction with alltrans retinoic acid (ATRA),trichostatin A (TSA) or ATRA combined with TSA.MethodsAfter the induction with ATRA,TSA,or ATRA combined with TSA in different concentrations for 96 h,the iodine uptake of FTC-133 cells was observed.The concentrations for different groups were as follows:ATRA 1.0 ×10-6 mol/L(Alow group),ATRA 1.0 × 10-4 mol/L(Ahigh group),TSA 1.65 ×10-7 mol/L(T group),Alow +T group,Ahigh +T group and ethanol (control group).Cell quantities and morphology were observed by HE staining.FTC-133 cells were subcutaneously injected into nude mice.Twelve nude mice were randomly divided into 4 groups after tumor formation:ATRA group (2 mg/kg,intragastric administration),TSA group (10 mg/kg,intraperitoneal injection),combined therapy group (ATRA + TSA,the same doses as above) and saline control group (10 ml/kg,intragastric and intraperitoneal administration,respectively).Drugs were administered to the tumor-bearing mice according to the mouse body mass daily.At the 22nd day,the tumor-bearing mice were injected with 37 MBq 131I intraperitoneally.The biodistribution of 131I and gamma imaging were performed at 4,6,12 and 24 h after the injection respectively.Histopathological examinations of the tumor samples were taken after imaging completion.The results were analyzed by analysis of variance (ANOVA) with SPSS 13.0.ResultsThe cellular iodine uptake were (23 885 ± 616.0 ) and ( 13 849 ±728.2) counts · min-1 · 10-6 cells in the Alow + T group and Ahigh + T group respectively,and the data were (985 ± 84.2) - ( 17 600 ± 782.7 ) counts · min-1 · 10-6 in the other groups ( F =600.879,P ＜0.001 ).The ％ ID/g of tumor at 6 h was 6.17 ±0.46 in the combined group and it increased to 9.34 ±0.61 at 12 h and 11.19 ± 0.98 at 24 h.The ％ ID/g of tumor in the other groups were from ( 1.97 ± 0.34)to (5.14 ± 0.65 ).The tumor qualities of the 4 groups were significantly different ( F =3.723,P ＜ 0.05 ).ConclusionThe iodine uptake of the tumor could be enhanced in the tumor-bearing mice administered with ATRA combined with TSA,a potential way for treating follicular thyroid carcinoma.
ABSTRACT
<p><b>BACKGROUND AND OBJECTIVE</b>The effectiveness rate of all-trans-retinoic acid (RA) is only about 30% in the clinical application of inducing thyroid carcinoma differentiation. In addition, there are severe toxic side effects, which limit its clinical application. Phase I-III clinical studies have been conducted on the combined application of two or more kinds of inductors in tumors. Nevertheless, the combination of RA with histone deacetylase inhibitors is rarely reported. This article studied the effects of differentiation for papillary thyroid carcinoma and follicular thyroid carcinoma cell lines induced by RA combined with trichostatin A (TSA), enhancing the effect of induction, while reducing the toxic side effects of a single drug, to provide a theoretical basis for preclinical trials.</p><p><b>METHODS</b>After incubation with RA combined with TSA, K1 and FTC-133 were grouped into Group 1 (RA 10(-4) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 2 (RA 1 x 10(-4) mol/L plus TSA 3.31 x 10(-7) mol/L), Group 3 (RA 10(-5) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 4 (RA 1 x10(-5) mol/L plus TSA 3.31 x 10(-7) mol/L) by four varied concentrations and three time points (12 h, 24 h, and 48 h). The cell proliferation, conformation, toxic effect, and induced differentiation on K1 and FTC-133 cell lines were studied microscopically with hematoxylin-eosin (HE) to observe cell quantity and morphology, methyl-thiazolyl-tetrazolium (MTT) to calculate cell survival rates, and electrochemiluminescence analysis measuring in vitro thyroglobulin (Tg) levels.</p><p><b>RESULTS</b>The research showed that K1 and FTC-133 cells had cell spacing increases, with an outer edge of smooth, nuclear chromatin condensation after RA combined TSA. Survival rate were assessed by an analysis of variance (ANOVA) by concentration and time point, F values of K1 and FTC-133 were 23.52 and 170.14, and 57.09 and 224.35, respectively. There were significant differences for both cells (P < 0.01). The SNK analysis indicated that survival rates were in the order of Group 2 < Group 1 < Group 4 < Group 3. Tg was also assessed by ANOVA, F values of K1 were 69.63 and 101.07, and F values of FTC-133 were 79.77 and 81.72 (P < 0.01). Group 1 was compared with Group 3 of K1 and FTC-133 by the least significant difference (LSD) method, and there was no statistical difference between the two group (P = 0.06, 0.2, respectively; P > 0.05), yet a significant difference was seen between the other Groups.</p><p><b>CONCLUSIONS</b>Lower concentrations of RA combined with lower concentrations of TSA have both inhibited cell proliferation, decreased toxicity of the drugs, and increased the effect of K1 and FTC-133 cell differentiation. The mechanism of action may be that TSA has pretranscription DNA regulation and that RA has posttranscriptional signal regulation to enhance the effects of inhibited proliferation and differentiation of cells by transcription systems.</p>