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

    Authors

    J. Colon; M. R. Basha; R. Madero-Visbal; S. Konduri; C. H. Baker; L. J. Herrera; S. Safe; D. Sheikh-Hamad; A. Abudayyeh; B. Alvarado;M. Abdelrahim

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    Abbreviated Journal Title

    Invest. New Drugs

    Keywords

    Tolfenamic acid; c-Met; Sp proteins; Lung cancer; Tumor inhibition; GENE-EXPRESSION; HGF RECEPTOR; THERAPEUTIC INHIBITION; TRANSCRIPTION; FACTORS; ACTIVATION; MUTATIONS; INDUCTION; OVEREXPRESSION; CARCINOMA; APOPTOSIS; Oncology; Pharmacology & Pharmacy

    Abstract

    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.

    Journal Title

    Investigational New Drugs

    Volume

    29

    Issue/Number

    1

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    41

    Last Page

    51

    WOS Identifier

    WOS:000285882400005

    ISSN

    0167-6997

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