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

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Summary

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Cancer Research Institute, M. D. Anderson Cancer Center Orlando, Orlando, FL, 32806, USA

    Jimmie Colon, Md. Riyaz Basha, Rafael Madero-Visbal, Santhi Konduri, Cheryl H. Baker, Luis J. Herrera, Beatrice Alvarado & Maen Abdelrahim

  2. Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA

    Cheryl H. Baker & Maen Abdelrahim

  3. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA

    Stephen Safe

  4. Division of Nephrology, Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA

    David Sheikh-Hamad & Ala Abudayyeh

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  1. Jimmie Colon
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Correspondence to Maen Abdelrahim.

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Jimmie Colon and Md. Riyaz Basha have equal contributions.

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Colon, J., Basha, M.R., Madero-Visbal, R. et al. Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. Invest New Drugs 29, 41–51 (2011). https://doi.org/10.1007/s10637-009-9331-8

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