chrysin and Thyroid-Neoplasms

Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC.. The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo.. Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis.. The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cell Proliferation; Flavonoids; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Male; Mice; Mice, Nude; Poly(ADP-ribose) Polymerases; Receptor, Notch1; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcription Factor HES-1; Xenograft Model Antitumor Assays

Anaplastic thyroid cancer (ATC) is an undifferentiated, aggressive malignancy, for which there are no effective therapies. Though ATCs only make up less than 2% of all thyroid cancer cases, they represent over half of the thyroid cancer-related deaths. Chrysin, a natural flavonoid, has recently been reported as a potential anti-cancer agent. However, the effect of this compound on ATC cells is not known. Thus, in this study, we evaluated the antiproliferative nature of chrysin in ATC cells.. HTH7 and KAT18 cells, derived from patients with ATC, were treated with chrysin (25-50 μM) for up to 6 d. Cell proliferation was measured every 2 d using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Western blot analysis for molecular makers of apoptosis was carried out to investigate the effect and mechanism of Chrysin on ATC.. Chrysin inhibited proliferation of HTH7 and KAT18 in a dose- and time-dependent manner. HTH7 and KAT18 cells with Chrysin treatment showed a significant increase in cleaved caspase-3, cleaved PolyADP Ribose Polymerase (PARP), along with a decrease in cyclin D1, Mcl-1, and XIAP. Furthermore, the ratio of Bax to Bcl-2 expression in ATC cells revealed an increase after the treatment.. Chrysin inhibits growth in ATC cells via apoptosis in vitro. Therefore, the natural flavonoid chrysin warrants further clinical investigation as a new potential drug for the treatment for ATC.

Topics: Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Flavonoids; Humans; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; X-Linked Inhibitor of Apoptosis Protein