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Phenylacetate inhibits growth and vascular endothelial growth factor secretion in human thyroid carcinoma cells and
E Kebebew1, M G Wong, A E Siperstein
1University of California, San Francisco, School of Medicine, 94143-1674, USA.
Abstract:
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 G0-1 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.
Insights
Phenylacetate shows antiproliferative effects in thyroid cancer cells, inhibiting growth and vascular endothelial growth factor secretion. This suggests potential as a novel therapy for differentiated thyroid cancer, especially when conventional treatments fail.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Phenylacetate demonstrates tumor growth inhibition and differentiation modulation across various cancers.
- Its effects on gene expression, protein prenylation, and glycosylation occur at safe human-use concentrations.
Purpose of the Study:
- To evaluate the antineoplastic and differentiation effects of phenylacetate on follicular cell-derived thyroid cancer cell lines in vitro.
- To investigate phenylacetate's impact on thyroid-stimulating hormone (TSH) response, radioactive iodine uptake, thyroglobulin secretion, and vascular endothelial growth factor (VEGF) secretion.
Main Methods:
- Treatment of five thyroid carcinoma cell lines with phenylacetate at concentrations of 2.5-10 mmol/L.
- Assessment of cell cycle arrest (G0-G1 phase) and cytostatic effects.
- Measurement of TSH-stimulated growth, radioactive iodine (125I) uptake, thyroglobulin secretion, and VEGF secretion.
Main Results:
- Phenylacetate induced early growth inhibition and cytostatic effects, arresting cells in the G0-G1 phase.
- It decreased TSH-stimulated growth, increased 125I uptake in two cell lines, and inhibited thyroglobulin secretion.
- Phenylacetate significantly inhibited VEGF secretion, a glycoprotein crucial for cellular excretion.
Conclusions:
- Phenylacetate exhibits antiproliferative effects on thyroid cancer cells, with variable impacts on differentiation.
- Inhibition of VEGF secretion by phenylacetate may contribute to observed antiangiogenic effects.
- Phenylacetate's low toxicity and demonstrated efficacy suggest its potential utility in treating differentiated thyroid cancer, either as an alternative to conventional therapy or as an adjunct to radioactive iodine therapy.