related:
1: Carcinogenesis. 2009 Apr 30. [Epub ahead of print]
Links
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.
The nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with IC(50) 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 hr 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 (VEGF) 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/d) 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.