Investigational New Drugs

, Volume 29, Issue 1, pp 41–51 | Cite as

Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice

  • Jimmie Colon
  • Md. Riyaz Basha
  • Rafael Madero-Visbal
  • Santhi Konduri
  • Cheryl H. Baker
  • Luis J. Herrera
  • Stephen Safe
  • David Sheikh-Hamad
  • Ala Abudayyeh
  • Beatrice Alvarado
  • Maen Abdelrahim


The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models. TA in a dose dependent manner inhibited proliferation and cell viability of two different lung cancer cells, A549 and CRL5803. TA treatment for 48 h significantly decreased the expression of Sp1, Sp3 and Sp4. The hepatocyte growth factor receptor, c-Met is overexpressed in a variety of cancers including lung cancer and Sp proteins mediate the regulation of c-Met. TA diminished the expression of c-Met protein and modulates its downstream signaling pathway. Furthermore, TA treatment significantly increased the number of apoptotic cells and pro-apoptotic markers c-PARP and Bax confirming the activation of apoptotic pathways. In vivo studies using the orthotopic mice model for lung cancer showed that TA (25 mg/kg/2 days and 50 mg/kg/2 days) resulted in a dose dependent decrease in tumor formation. The immunohistochemical staining of lung tissue showed high expression of Sp1, Sp3, Sp4, c-Met and phospho Met in control group and a dose dependent decrease in TA treated groups. The crucial findings of this study support that targeting c-Met with a potent inhibitor of Sp proteins is a robust strategy for the implications in lung cancer treatment and TA can serve as a therapeutic agent for this devastating disease.


Tolfenamic acid c-Met Sp proteins Lung cancer Tumor inhibition 



Authors thank M. D. Anderson Cancer Center Orlando’s Cancer Research Institute for providing necessary financial and technical assistance. The assistance of Donna Schade and Beth Isley is greatly appreciated.

Supplementary material

10637_2009_9331_MOESM1_ESM.ppt (610 kb)
ESM 1(PPT 609 kb)


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jimmie Colon
    • 1
  • Md. Riyaz Basha
    • 1
  • Rafael Madero-Visbal
    • 1
  • Santhi Konduri
    • 1
  • Cheryl H. Baker
    • 1
    • 2
  • Luis J. Herrera
    • 1
  • Stephen Safe
    • 3
  • David Sheikh-Hamad
    • 4
  • Ala Abudayyeh
    • 4
  • Beatrice Alvarado
    • 1
  • Maen Abdelrahim
    • 1
    • 2
  1. 1.Cancer Research InstituteM. D. Anderson Cancer Center OrlandoOrlandoUSA
  2. 2.Burnett School of Biomedical SciencesUniversity of Central FloridaOrlandoUSA
  3. 3.Institute of Biosciences and TechnologyTexas A&M University Health Science CenterHoustonUSA
  4. 4.Division of Nephrology, Department of Internal MedicineBaylor College of MedicineHoustonUSA

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