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Prostate. 2012 Nov;72(15):1648-58. doi: 10.1002/pros.22518. Epub 2012 Apr 2.

Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer.

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  • 1Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida 32827, USA.

Abstract

BACKGROUND:

Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non-steroidal anti-inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti-cancer activity of TA using in vitro and in vivo models for prostate cancer.

METHODS:

The anti-proliferative efficacy of TA was evaluated using DU-145, PC-3, and LNCaP cells. PC-3 cells were treated with DMSO or 50 µM TA for 48 hr. Whole cell lysates were evaluated for the expression of Sp1, survivin, c-PARP, Akt/p-Akt, c-Met, cdk4, cdc2, cyclin D3, and E2F1 by Western blot analysis. Cell invasion was assessed by Boyden-chamber assay and flow cytometry analysis was used to study apoptosis and cell cycle distribution. An orthotopic mouse model for prostate cancer with PC-3-Luc cells was used to study the in vivo effect of TA.

RESULTS:

TA inhibited the expression of Sp1, c-Met, p-Akt, and survivin; increased c-PARP expression and caspases activity in PC-3 cells. TA caused cell arrest at G(0) /G(1) phase accompanied by a decrease in cdk4, cdc2, cyclin D3, and E2F1 and an increase in critical apoptotic markers. TA augmented annexin-V staining, caspase activity, and c-PARP expression indicating the activation of apoptotic pathways. TA also decreased PC-3 cell invasion. TA significantly decreased the tumor weight and volume which was associated with low expression of Sp1 and survivin in tumor sections.

CONCLUSION:

TA targets critical pathways associated with tumorigenesis and invasion. These pre-clinical data strongly demonstrated the anti-cancer activity of TA in prostate cancer.

Copyright © 2012 Wiley Periodicals, Inc.

[PubMed - indexed for MEDLINE]
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