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

Hellsten, Rebecka LU ; Johansson, Martin H LU ; Dahlman, Anna K LU ; Dizeyi, Nishtman LU ; Sterner, Olov LU and Bjartell, Anders LU (2008) In The Prostate 68(3). p.269-280
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DU-145, PC-3, natural products, LNCaP, xenograft
in
The Prostate
volume
68
issue
3
pages
269 - 280
publisher
John Wiley & Sons
external identifiers
  • pmid:18163422
  • wos:000253242600005
  • scopus:39449098191
ISSN
0270-4137
DOI
10.1002/pros.20699
language
English
LU publication?
yes
id
8eec9eed-5477-4862-ae10-d1f46e59d93c (old id 1214953)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18163422?dopt=Abstract
date added to LUP
2008-08-14 15:04:33
date last changed
2017-11-12 03:32:58
@article{8eec9eed-5477-4862-ae10-d1f46e59d93c,
  abstract     = {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 &lt; 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.},
  author       = {Hellsten, Rebecka and Johansson, Martin H and Dahlman, Anna K and Dizeyi, Nishtman and Sterner, Olov and Bjartell, Anders},
  issn         = {0270-4137},
  keyword      = {DU-145,PC-3,natural products,LNCaP,xenograft},
  language     = {eng},
  number       = {3},
  pages        = {269--280},
  publisher    = {John Wiley & Sons},
  series       = {The Prostate},
  title        = {Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3.},
  url          = {http://dx.doi.org/10.1002/pros.20699},
  volume       = {68},
  year         = {2008},
}