• Open Access

Apoptotic effect of tolfenamic acid in androgen receptor-independent prostate cancer cell and xenograft tumor through specificity protein 1

Authors

  • Eun-Sun Choi,

    1. Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju
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    • These authors contributed equally to this paper.

  • Jung-Hyun Shim,

    1. Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan
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    • These authors contributed equally to this paper.

  • Ji-Youn Jung,

    1. Department of Companion and Laboratory Animal Science, Kongju National University, Yesan
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  • Hyeong-Jin Kim,

    1. Department of Companion and Laboratory Animal Science, Kongju National University, Yesan
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  • Kyeong-Hee Choi,

    1. Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju
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  • Ji-Ae Shin,

    1. Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju
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  • Jeong-Seok Nam,

    1. Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, Korea
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  • Nam-Pyo Cho,

    Corresponding author
    1. Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju
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  • Sung-Dae Cho

    Corresponding author
    1. Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju
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To whom correspondence should be addressed.
E-mails: efiwdsc@chonbuk.ac.kr; npcho@chonbuk.ac.kr

Abstract

Tolfenamic acid (Tol) is a non-steroidal anti-inflammatory drug that was reported to exhibit anticancer activity in pancreatic and colorectal cancer models. This study examined the role of Tol in the death regulation of PC-3 and DU145 human androgen-independent prostate cancer cells. The results showed that Tol inhibited cell growth and induced apoptosis, as evidenced by nuclear fragmentation and cleaved caspase 3 and poly(ADP-ribose) polymerase. Tol suppressed the specificity protein 1 (Sp1) protein in both PC-3 and DU145 cells. Tol also attenuated Sp1 mRNA and its promoter activity in DU145 cells, but did not alter them in PC-3 cells, indicating that Tol degrades Sp1 protein in these cells. Tol also downregulated protein levels, mRNA levels and promoter activities of survivin and myeloid cell leukemia-1, which are downstream targets of Sp1. The expressions of survivin and Mcl-1 and cancer cell growth were lower in the PC-3 cells treated with Sp1 interfering RNA and mithramycin A. Moreover, an oral injection of Tol decreased tumor growth and downregulated the Sp1 protein in athymic nude mice bearing DU145 cell xenografts without hepatotoxicity. Overall, Tol downregulates the Sp1 protein to inhibit growth and induce apoptosis in androgen-refractory prostate cancers, both in vitro and in vivo, that show resistance against many chemotherapeutic agents. (Cancer Sci 2011; 102: 742–748)

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