Anti-proliferative effects of a novel isoflavone derivative in medullary thyroid carcinoma: an in vitro study.

Currently available treatments for patients with medullary thyroid carcinoma (MTC) with residual or recurrent disease after primary surgery have low efficacy rates. In view of the possible role of estrogen in the development of thyroid neoplasia, we explored whether proliferation of the human MTC TT cell line, might be curbed by carboxy-daidzein-tBoc (cD-tBoc), a novel isoflavone derivative. Estrogen receptor (ER) alpha mRNA expression in IT cells was more abundant than ER beta, with a ratio of 48:1. Estradiol-17 beta (E2) increased DNA synthesis in a dose dependent manner. [H-3]-thymidine incorporation was also stimulated by the ER beta agonist DPN and the ER alpha agonist PPT. cD-tBoc inhibited TT cell growth as assessed by thymidine incorporation, XTT assay, and microscopic analysis of culture wells. Creatine kinase specific activity, a marker of the modulatory effects of estrogen on cell energy metabolism, was likewise inhibited. The inhibitory effect of cD-tBoc on [H-3]-thymidine incorporation could be blocked by the ER beta antagonist PTHPP but not by the ER alpha antagonist MPP, suggesting that the antiproliferative effect of cD-tBoc on these cells is mediated through ER beta. Furthermore, cD-tBoc potently increased apoptosis and cell necrosis. Co-incubation with the antiapoptotic agent Z-VAD-FMK reversed the growth inhibitory effect elicited by cD-tBoc. These results support the hypothesis that estrogens are involved in the proliferation of MTC. The potent anti-proliferative effects mediated by isoflavone derivatives in the human MTC cell line TT suggest and that this property may be utilized to design effective anti-neoplastic agents. (C) 2012 Elsevier Ltd. All rights reserved.