Zusammenfassung
Einleitung
Phytoöstrogene sind Wirkstoffe pflanzlichen Ursprungs mit antiproliferativem Potential bei Prostatakarzinom-Zellen, dessen Grundlage im Detail ungeklärt ist. Proliferation von PCa-Zellen wird vor allem durch den Androgenrezeptor (AR) und seinen Co-Aktivator, dem Prostate-derived Ets Factor (PDEF) vermittelt, die wiederum den IGF-1 Rezeptor (IGF-1-R) steuern. Phytoöstrogene greifen in diesen Prozess ein. Die aktuelle Studie verdeutlicht dies exemplarisch anhand der Wirkung von Tectorigenin aus Belamcanda chinensis.
Material und Methode
Androgen-sensitive PCa-Zellen der LNCaP-Linie wurden über 24 Stunden mit Tectorigenin 100 µM behandelt und die mRNA-Expression von AR, PSA, PDEF, Telomerase Reverse Transcriptase (hTERT), Tissue-Inhibitor of Matrix-Metalloproteinase-3 (TIMP-3) und des IGF-1-R durch Real-Time-PCR bestimmt. Die Aktivität von PSA, Telomerase und IGF-1-R wurde auch auf Proteinebene bestimmt. Weiterhin wurde in-vivo der Einfluss einer Diät mit Rohextrakt Belamcanada chinensis im Vergleich zu sojafreier Diät auf das Wachstum von subkutan injizierten Prostatakarzinomzellen in Nacktmäusen untersucht.
Ergebnisse
Bei den LNCaP bewirkte Tectorigenin eine Herunterregulierung der Genexpression von PDEF und PSA. Die Aktivität der hTERT war vermindert. Es zeigte sich eine verminderte Genexpression des IGF-1-R. Auf Proteinebene fand sich eine verminderte Aktivität von PSA, hTERT und IGF-R-1. Die Genexpression von TIMP-3 war unter dem Einfluss von Tectorigenin deutlich erhöht. Bei den Nacktmäusen fand sich neben einer verminderten Inzidenz ein verringertes Tumorvolumen unter Diät mit Belamcanda chinensis.
Schlussfolgerung
Tectorigenin zeigte eine Hemmung der IGF-1-R-vermittelten Proliferation bei PCa-Zellen, durch eine vom AR unabhängige Modulation der Aktivität von PDEF. Über Aktivierung von TIMP-3 hat Tectorigenin proapoptotische Effekte und hemmt die Gewebeinvasivität des Tumors. Phytoöstrogene könnten somit eine interessante Option in der Therapie insbesondere des fortgeschrittenen Prostatakarzinoms darstellen.
Abstract
Introduction
Phytoestrogenes are plant-derived compounds that have been shown to exert an antiproliferative potential on prostate cancer cells, although the exact mechanisms are still unclear. In prostate cancer cells proliferation is regulated by modulation of the IGF-1 receptor (IGF-R-1) by the androgen receptor (AR) and its co-activator prostate derived Ets factor (PDEF). Phytooestrogenes interact with these mechanisms as demonstrated exemplarily in the presented study with the isoflavone tectorigenin derived from Belamcanda chinensis.
Material and methods
Cultured androgen-sensitive LNCaP prostate cancer cells were treated with tectorigenin of 100 µM for 24 hours. The mRNA-expression of AR, PSA, PDEF, hTERT, TIMP-3 and IGF-R-1 were quantified by real-time RT-PCR. Furthermore, the expression or activity of PSA, telomerase and IGF-R-1 was measured on the protein level. In addition, we investigated in nude mice the influence of a diet of extracts of Belamcanda chinensis on the growth of subcutaneously injected LNCaP cells versus a control group of animals fed with a soy-free diet.
Results
In cultured LNCaP cells treatment with tectorigenin resulted in a significant down-regulation of the gene expression of AR, PDEF, PSA, IGF-R-1 and hTERT. On the protein level PSA secretion and the activity of telomerase and IGF-R-1 expression was also decreased. The gene expression of TIMP-3 was distinctly up-regulated by tectorigenin. Nude mice fed with Belamcanda chinensis extract showed a significantly decreased incidence and tumor growth compared to controls.
Conclusions
Tectorigenin shows an inhibition of the IGF-1-R modulated cell proliferation of PCa-Cells, due to modulation of the activity the co-activator PDEF independently from the AR. Furthermore, tectorigenin has pro-apoptotic effects and decreases tissue invasion by up-regulation of TIMP-3. Therefore, phytooestrogenes are an interesting option in the therapy of prostate especially advanced prostate cancer.
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Literatur
Adlercreutz H, Mazur W (1997) Phyto-oestrogenes and Western diseases. Ann Med 10: 95–120
Bond M, Murphy G, Bennet MR, Newby AC, Baker AH (2002) Tissue inhibitor of metalloproteinase-3 induces Fas-associated death domain-dependent type II apoptototic pathway. J Biol Chem 277: 1387–1395
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL (2004) Molecular deteminants of resistance to antiandrogen therapy. Nat Med 10: 33–39
Cos P, De Bruyne T, Apers S, Van den Berghe D, Pieters L, Vlietinck AJ (2003) Phytooetrogenes: Recent developments. Planta Med 69: 589–599
Denis L, Morton MS, Grffiths K (1999) Diet and its preventive role in prostatic disease. Eur Urol 35: 377–387
Gao S, Liu GZ, Wang Z (2004) Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells. Prostate 59: 214–225
Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Burfeind P (2004) Blockade of the type I IGF receptor expression in human prostate cancer cells inhibits proliferation and invasion, up-regulates IGF binding protein-3, and suppresses MMP-2 expression. J Pathol 202: 50–59
Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM (2002) Expression of the type-1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 62: 2942–2950
Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF (2002) Establishment and characterization of androgen-independent human prostate cancer LNCaP cell modell. Prostate 50: 222–235
Jung SH, Lee YS, Lee S, Lim SS, Kim YS, Ohuchi K, Shin KH (2003) Anti-angiogenic and anti-tumor activities of isoflavonoids from the rhizomes of Belamcanda chinensis. Planta Med 69: 617–622
Lee KT, Sohn IC, Kim YK et al. (2001) Tectorigenin, an isoflavone of Pueraria thunbergiana Benth, induces differentiation and apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull 24: 1117–1121
Morrissey C, Bektic J, Spengler B et al. (2004) Phytooestrogenes derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro. J Urol 172: 2426–2433
Murphy G, Knauper V, Lee MH et al. (2003) Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis. the specificity is the detail. Biochem Soc Symp 70: 65–80
Nanni S, Narducci M, Della Pietra L et al. (2002) Signalling through estrogen receptors modulates telomerase activity in human prostate cancer. J. Clin Invest 110: 219–227
Nelson PS, Montgomery B (2003) Unconventional therapy for prostate cancer: good, bad, or questionable ? Nat Rev Cancer 3: 845–858
Pandini G, Mineo R, Frasca F, Roberts CTJ, Marcelli M, Vigneri R, Belfiore A (2005) Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res 65: 1849–1857
Taplin ME, Balk SP (2004) Androgen receptor: A key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem 91: 483–490
Thelen P, Scharf JG, Burfeind P, Hemmerlein B, Wuttke W, Ringert RH, Seidlova-Wuttke D (2005) Tectorigenin and other phytochemicals extracted from leopard lily Belamcanda chinensis affect new and established targets for therapies in prostate cancer. Carcinogenesis (im Druck)
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Thelen, P., Seseke, F., Ringert, RH. et al. Das pharmakologische Potential von Phytoöstrogenen in der Therapie des Prostatakarzinoms. Urologe 45, 195–201 (2006). https://doi.org/10.1007/s00120-005-0932-3
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DOI: https://doi.org/10.1007/s00120-005-0932-3