Carcinogenesis. 2009 Jul;30(7):1193-201. Epub 2009 Apr 30.
Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met.
Papineni S, Chintharlapalli S, Abdelrahim M, Lee SO, Burghardt R, Abudayyeh A, Baker C, Herrera L, Safe S.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits
proliferation of SEG-1 and BIC-1 esophageal cancer cells with
half-maximal growth inhibitory concentration values of 36 and 48 muM,
respectively. TA also increased Annexin V staining in both cell lines,
indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells
with TA for up to 72 h decreased expression of specificity protein (Sp)
transcription factors Sp1, Sp3 and Sp4 and this was accompanied by
decreased expression of the well-characterized Sp-regulated genes
cyclin D1, vascular endothelial growth factor and survivin. TA also
decreased hepatocyte growth factor receptor, (c-Met), a receptor
tyrosine kinase that is overexpressed in esophageal cancer cells and
tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4
by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met
expression, demonstrating that c-Met is an Sp-regulated gene in
esophageal cancer cells. Sp1 was overexpressed in esophageal cancer
cells and tumors and increased Sp1 staining was observed in esophageal
tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and
weight in athymic nude mice bearing SEG-1 cells as xenografts and this
was accompanied by increased apoptosis and decreased Sp1 and c-Met
staining in tumors from treated mice. Thus, TA-dependent downregulation
of Sp transcription factors and c-Met defines a novel chemotherapeutic
approach for treatment of esophageal cancer.