Phenylacetate inhibits growth and vascular endothelial growth factor secretion in human thyroid carcinoma cells and modulates their differentiated function

There is increasing evidence that phenylacetate inhibits growth and modulat es 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 phenylace tate 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 thyro id carcinoma cells arrested in the G(0-1) cell phase. When evaluating the e ffect of phenylacetate on the differentiated functions of thyroid carcinoma cells, phenylacetate exposure: 1) decreased the TSH (10 mU/mL) growth resp onse; 2) increased radioactive iodine (I-125) uptake in two out of five cel l lines; and 3) inhibited thyroglobulin secretion. Phenylacetate also inhib ited the secretion of vascular endothelial growth factor (a glycoprotein de pendent on glycosylation for efficient cellular excretion) from the thyroid cancer cell lines. Our results support that phenylacetate has an antiproli ferative Effect in many cell types, but the differentiating effects were no t uniform. Importantly, we have identified that phenylacetate inhibits the secretion of vascular endothelial growth factor, which possibly mediates th e antiangiogenic effects observed in vivo. Because of the minimal toxicity associated with phenylacetate treatment in humans, at concentrations we sho w to have a significant antineoplastic effect in thyroid carcinoma cells, p henylacetate could be useful in patients with differentiated thyroid cancer who fail conventional therapy or as an adjuvant to radioactive iodine ther apy in patients with aggressive tumors.