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SMIT
Differential effects of natural flavonoids on growth and iodide content in a human Na*/I- symporter-transfected follicular thyroid carcinoma cell line.Schroder-van der Elst JP, van der Heide D, Romijn JA, Smit JW. Eur J Endocrinol. 2004 Apr;150(4):557-64.
"OBJECTIVE: Natural flavonoids (plant pigments) have been shown to inhibit thyroid peroxidase (TPO) in vitro and the growth of thyroid cancer cell lines. We have studied the role of flavonoids on the iodide transport and the growth of the human follicular thyroid cancer cell line (FTC133) which was stably transfected with the human Na(+)/I(-) symporter (hNIS).
DESIGN AND METHODS: Cells were treated with flavonoids (0.5-50 microM) for 0, 2, 4 and 6 days; (125)I content and (125)I efflux of the cells and DNA content were measured.
RESULTS: Cell growth was inhibited significantly at day 6 by most flavonoids. Eight out of ten flavonoids decreased the (125)I content of the cells at day 4. Morin did not influence the (125)I content of the cells and, surprisingly, myricetin increased the (125)I content of the cells. Kaempferol, apigenin, luteolin and F21388 decreased NIS mRNA expression after 15, 29 and 48 h; after 96 h NIS mRNA returned to normal.
CONCLUSION: As TPO is not present in this
cell line, the effects of the flavonoids on the iodide uptake are
not related to organification. Myricetin was the only flavonoid
studied that increased the influx and decreased the efflux of
iodide. The effect of myricetin (decreased growth and increased
retention of iodide) can be of therapeutic value in the
radioiodide treatment of thyroid carcinoma.
Dietary flavonoids and iodine metabolism.Schroder-van der Elst JP, Smit JW, Romijn HA, van der Heide D. Biofactors. 2003;19(3-4):171-6. [abstract only]
"Flavonoids have inhibiting effects on the proliferation of cancer cells, including thyroidal ones. In the treatment of thyroid cancer the uptake of iodide is essential. Flavonoids are known to interfere with iodide organification in vitro, and to cause goiter. The influence of flavonoids on iodine metabolism was studied in a human thyroid cancer cell line (FTC-133) transfected with the human sodium/iodide transporter (NIS). All flavonoids inhibited growth, and iodide uptake was decreased in most cells. NIS mRNA expression was affected during the early hours after treatment, indicating that these flavonoids can act on NIS. Pendrin mRNA expression did not change after treatment. Only myricetin increased iodide uptake. Apeginin, luteolin, kaempferol and F21388 increased the efflux of iodide, leading to a decreased retention of iodide. Instead myricetin increased the retention of iodide; this could be of use in the radioiodide treatment of thyroid cancer."
Iodide kinetics and experimental (131)I therapy in a xenotransplanted human sodium-iodide symporter-transfected human follicular thyroid carcinoma cell line.Smit JW, Schroder-van der Elst JP, Karperien M, Que I, Stokkel M, van der Heide D, Romijn JA. J Clin Endocrinol Metab. 2002 Mar;87(3):1247-53.
"Uptake of iodide is a prerequisite for radioiodide therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium-iodide symporter (hNIS). We studied whether transfection of hNIS into the hNIS-deficient follicular thyroid carcinoma cell line FTC133 restores the in vivo iodide accumulation in xenografted tumors and their susceptibility to radioiodide therapy. In addition, the effects of low-iodide diets and thyroid ablation on iodide kinetics were investigated.
"Tumors were established in nude mice injected with the hNIS-transfected cell line FTC133-NIS30 and the empty vector transfected cell line FTC133-V4 as a control. Tumors derived from FTC133-NIS30 in mice on a normal diet revealed a high peak iodide accumulation (17.4% of administered activity, measured with an external probe) as compared with FTC133-V4 (4.6%). Half-life in FTC133-NIS30 tumors was 3.8 h. In mice kept on a low-iodide diet, peak activity in FTC133-NIS30 tumors was diminished (8.1%), whereas thyroid iodide accumulation was increased. In thyroid-ablated mice kept on a low-iodide diet, half-life of radioiodide was increased considerably (26.3 h), leading to a much higher area under the time-radioactivity curve than in FTC133-NIS30 tumors in mice on a normal diet without thyroid ablation. Experimental radioiodide therapy with 2 mCi (74 MBq) in thyroid-ablated nude mice, kept on a low-iodide diet, postponed tumor development (4 wk after therapy, one of seven animals revealed tumor vs. five of six animals without therapy). However, 9 wk after therapy, tumors had developed in four of the seven animals. The calculated tumor dose was 32.2 Gy.
"We conclude that hNIS transfection into a hNIS-defective thyroid carcinoma cell line restores the in vivo iodide accumulation. The unfavorable iodide kinetic characteristics (short half-life) can be partially improved by conventional conditioning with thyroid ablation and low-iodide diet, leading to postponed tumor development after radioiodide therapy. However, to achieve sufficient radioiodide tumor doses for therapy, further strategies are necessary, aiming at the mechanisms of iodide efflux in particular."
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