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Phenylacetate Inhibits Growth and Vascular Endothelial Growth Factor Secretion in Human Thyroid Carcinoma Cells and Modulates Their Differentiated Function¹

University of California, San Francisco, School of Medicine; University of California, San Francisco/Mount Zion Medical Center, Department of Surgery (E.K., M.G.W., A.E.S., O.H.C.); and San Francisco Veterans Affairs Medical Center, Surgical Services (Q.-Y.D.)

Address all correspondence and requests for reprints to: Orlo H. Clark, University of California, San Francisco/Mount Zion Medical Center, Department of Surgery, 1600 Divisadero Street, San Francisco, California 94143-1674. E-mail: clarkaa{at}mzsurgery.his.ucsf.edu

There is increasing evidence that phenylacetate inhibits growth and modulates differentiation in a variety of tumors with effects on gene expression, and protein prenylation and glycosylation at concentrations that have been safely used in humans. We evaluated the antineoplastic effects of phenylacetate in five thyroid cancer cell lines of follicular cell origin in vitro. We found early growth inhibition occurred with phenylacetate treatment at a dose of 2.5–10 mmol/L. The growth inhibition was cytostatic with the thyroid carcinoma cells arrested in the G_0–1 cell phase. When evaluating the effect of phenylacetate on the differentiated functions of thyroid carcinoma cells, phenylacetate exposure: 1) decreased the TSH (10 mU/mL) growth response; 2) increased radioactive iodine (¹²⁵I) uptake in two out of five cell lines; and 3) inhibited thyroglobulin secretion. Phenylacetate also inhibited the secretion of vascular endothelial growth factor (a glycoprotein dependent on glycosylation for efficient cellular excretion) from the thyroid cancer cell lines. Our results support that phenylacetate has an antiproliferative effect in many cell types, but the differentiating effects were not uniform. Importantly, we have identified that phenylacetate inhibits the secretion of vascular endothelial growth factor, which possibly mediates the antiangiogenic effects observed in vivo. Because of the minimal toxicity associated with phenylacetate treatment in humans, at concentrations we show to have a significant antineoplastic effect in thyroid carcinoma cells, phenylacetate could be useful in patients with differentiated thyroid cancer who fail conventional therapy or as an adjuvant to radioactive iodine therapy in patients with aggressive tumors.

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