Chemopreventive effect of tolfenamic acid on KB human cervical cancer cells and tumor xenograft by downregulating specificity protein 1

Earlier studies have shown that tolfenamic acid (Tol) exhibits anticancer activity in several cancer models by inhibiting tumor growth and angiogenesis. However, the chemopreventive effect of Tol on a cervical cancer model and the underlying mechanism of action are unknown. In this study, Tol was found to inhibit cell proliferation by inducing apoptosis without affecting cyclo-oxygenase 2 expression, but ampiroxicam did not. Tol decreases the specificity protein 1 (Sp1) mRNA and its promoter activity in KB cervical cancer cells, and the downregulation of Sp1 protein by affecting several proteins that contain GC-rich sites on their promoters. Studies using small interference RNA and an Sp1-specific inhibitor (mithramycin A) confirmed that the decrease in Sp1 by Tol affects survivin and p27. Tol also inhibited tumor growth and Sp1 protein in athymic nude mice xenografts. These results show that Tol could be a potent anticervical cancer drug that acts by regulating Sp1 protein and its downstream pathways.