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Carcinogenesis Advance Access published online on April 30, 2009
Carcinogenesis, doi:10.1093/carcin/bgp092
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tolfenamic Acid Inhibits Esophageal Cancer Through Repression of Specificity Proteins and c-Met

Sabitha Papineni1,*, Sudhakar Chintharlapalli2,*, Maen Abdelrahim3, Syng-ook Lee2, Robert Burghardt4, Ala Abudayyeh5, Cheryl Baker3, Luis Herrera3 and Stephen Safe1,2

1 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466
2 Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030-3303
3 Cancer Research Institute, M. D. Anderson Cancer Center Orlando, Orlando, FL 32806
4 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458
5 Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030

Correspondence should be sent to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, Tel: 979-845-5988 / Fax: 979-862-4929, Email: ssafe{at}cvm.tamu.edu

The nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with IC50 values of 36 and 48 µM, 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.

Key Words: Tolfenamic acid • c-Met • Sp proteins • esophageal cancer • cell inhibition • tumor inhibition

* Authors contributed equally.

Received February 19, 2009; revised April 6, 2009; accepted April 9, 2009.


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