Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF-1 receptor and androgen dependent growth of LAPC-4 prostate cancer cells

Charles J. Ryan, Marianna Zavodovskaya, Jack F. Youngren, Michael Campbell, Marc Diamond, Jeremy Jones, Laura Shiry, Geoffrey Allan, Betty A. Maddux, Ira D. Goldfine

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19 Scopus citations

Abstract

BACKGROUND. Nordihydroguaiaretic acid (NDGA) is an inhibitor of the IGF-1 receptor (IGF-1R) in breast and other cancers, and concomitantly inhibits tumor growth both in cultured cells and animals. The current study evaluates the effect of NDGA on the androgen-stimulated growth of human prostate cancer cells. METHODS. LAPC-4 prostate cancer cells in tissue culture were androgen starved for 3 days, 1 nM dihydrotestosterone (DHT) and other androgens were then added for up to 7 days, and cell proliferation measured. IGF-1R protein expression was measured by Western blot, and IGF-1R mRNA expression by quantitative PCR. IGF-1R receptor kinase activation was measured by ELISA. RESULTS. After 7 days, LAPC-4 growth was doubled by 1 nM DHT. NDGA had a rapid effect to inhibit IGF-1R autophosphorylation induced by IGF-1. DHT increased the expression of IGF-1R protein and mRNA levels. Maximal IGF-1R protein levels were observed 3 days after the addition of androgen. In addition, NDGA, at 10 μM or less, inhibited DHT-induced proliferation in both cells grown in plates and cells grown in soft agar. Androgen receptor (AR) studies by FRET revealed that NDGA had no conformational effects on the AR in response to ligand. CONCLUSIONS. NDGA blocks the DHT-induced growth of LAPC-4 prostate cancer cells by several mechanisms including rapid inhibition of the IGF-1R kinase, and a dose-dependent inhibition of androgen stimulation of IGF-1R expression. Clinical studies of this agent will determine its efficacy in the setting of androgen-dependent prostate cancer.

Original languageEnglish (US)
Pages (from-to)1232-1240
Number of pages9
JournalProstate
Volume68
Issue number11
DOIs
StatePublished - Aug 1 2008

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Keywords

  • Gene expression
  • Insulin-like growth factor 1
  • Insulin-like growth factor 1 receptor
  • NDGA
  • Prostate cancer
  • Tyrosine kinase

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Ryan, C. J., Zavodovskaya, M., Youngren, J. F., Campbell, M., Diamond, M., Jones, J., Shiry, L., Allan, G., Maddux, B. A., & Goldfine, I. D. (2008). Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF-1 receptor and androgen dependent growth of LAPC-4 prostate cancer cells. Prostate, 68(11), 1232-1240. https://doi.org/10.1002/pros.20789