Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway.

Tyrosine kinase receptors such as c-Met and its ligands are interesting therapeutic targets that have been reported to be involved in the progression of several types of cancers. Histone deacetylase inhibitor, valproic acid (VPA) is one such compound with promising anti-cancer properties. The current study was designed to evaluate the c-Met activity of VPA in thyroid carcinoma. A total 36 nu/nu mice with SW1736 cells-induced tumours were randomised into three treatment groups (5, 15, 30 mg/kg/day p.o. VPA; n = 9/group). Various cellular and enzymatic assays were performed to evaluate the dose-response relationship of VPA in c-Met inhibition. In vitro assays revealed that VPA (IC50, 5-26 nmol/l) shows c-Met phosphorylation and c-Met-dependent inhibition of cellproliferation. This causes inhibition of downstream signalling pathways in human thyroid cancer cell lines (SW1736, WRO). Additionally, VPA also showed anti-angiogenetic activity in HGF-stimulated endothelial cell. VPA showed significant reduction in tumour size in xenograft model (P = 0.023) with high levels of c-Met expression. The anticancer activity was found to be dose dependent and strongly correlated with c-Met expression. Thus, this novel finding paves way for investigation of new mechanism of action and its validation in clinical settings.