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Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3.

Author:
  • Rebecka Hellsten
  • Martin H Johansson
  • Anna K Dahlman
  • Nishtman Dizeyi
  • Olov Sterner
  • Anders Bjartell
Publishing year: 2008
Language: English
Pages: 269-280
Publication/Series: The Prostate
Volume: 68
Issue: 3
Document type: Journal article
Publisher: John Wiley & Sons

Abstract english

BACKGROUND: Signal transducer and activator of transcription 3 (Stat3) is constitutively active (phosphorylated) in several forms of cancer, including prostate cancer (PCa). Stat3 signaling may be an interesting target for cancer therapy since inhibition of this pathway mediates growth inhibition and apoptosis of these cells. In this study we investigated the in vitro and in vivo effects of the fungal metabolite galiellalactone, a direct inhibitor of Stat3, on PCa cells. METHODS: The human PCa cell lines DU145, PC-3, and LNCaP were used. Nude mice with subcutaneous PCa cell xenografts were subjected to daily intraperitoneal injections of galiellalactone for 3 weeks. The effect of galiellalactone on the induction of apoptosis of cultured PCa cells was investigated by Western blot analysis, immunocytochemistry, and annexin V staining. Effects of galiellalactone on Stat3 signaling were investigated by a luciferase reporter gene assay. Expression of Stat3 associated proteins and mRNA was investigated by Western blot and real-time quantitative PCR analysis. RESULTS: Galiellalactone induced apoptosis of p-Stat3 positive PCa cells (androgen-insensitive DU145 and PC-3) but not in cells lacking p-Stat3 (androgen-sensitive LNCaP). Galiellalactone inhibited Stat3-mediated luciferase activity (IC(50) approximately 5 microM) and reduced the expression of Bcl-2, Bcl-x(L), c-myc, and cyclin D1. Furthermore, galiellalactone significantly suppressed DU145 xenograft growth in vivo (42% growth reduction; P < 0.002) and reduced the relative mRNA expression of Bcl-x(L) and Mcl-1. CONCLUSIONS: Galiellalactone induced growth inhibition and apoptosis in androgen-insensitive PCa cells expressing p-Stat3. We suggest that galiellalactone is a potential anti-tumor lead against hormone-refractory PCa with constitutively active Stat3. Prostate 68: 269-280, 2008. (c) 2007 Wiley-Liss, Inc.

Keywords

  • Obstetrics, Gynecology and Reproductive Medicine
  • DU-145
  • PC-3
  • natural products
  • LNCaP
  • xenograft

Other

Published
  • Urological cancer, Malmö
  • Urological research, Malmö
  • ISSN: 0270-4137
Olov Sterner
E-mail: olov [dot] sterner [at] science [dot] lu [dot] se

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Faculty of Science

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