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Clin Cancer Res. 2007 Apr 1;13(7):2271-80.

The therapeutic and preventive effect of RRR-alpha-vitamin E succinate on prostate cancer via induction of insulin-like growth factor binding protein-3.

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  • 1Department of Urology , George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, New York 14642, USA.

Abstract

PURPOSE:

Insulin-like growth factor binding protein-3 (IGFBP-3) is a well-known antiproliferative and proapoptotic molecule in prostate cancer, suggesting that targeting IGFBP-3 might produce clinical benefits. In prostate cancer cells, RRR-alpha-vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis, yet the mechanisms remain to be elucidated. We hypothesize that the protective effects of VES in prostate cancer are mediated by IGFBP-3 up-regulation. Using prostate cancer models, the involvement of IGFBP-3 in the anticancer effect of VES was investigated.

EXPERIMENTAL DESIGN:

IGFBP-3 mRNA and protein were determined by real-time PCR and Western blotting in prostate cancer cells, xenografted tumors of nude mice, and prostate tumors of transgenic adenocarcinoma mouse prostate (TRAMP) mice. The serum levels of IGFBP-3 were assessed by ELISA. The importance of IGFBP-3 in VES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy.

RESULTS:

We found that VES induced IGFBP-3 mRNA and protein levels in human prostate cancer cell lines. Knockdown of IGFBP-3 by small interfering RNA attenuated VES-induced IGFBP-3 expression and VES-mediated antiproliferative and proapoptotic functions. Furthermore, administration of VES resulted in a significant therapeutic effect on LNCaP and PC3 xenografts and a preventive effect on tumorigenic progression in the TRAMP model without overt toxicity. Notably, the therapeutic and preventive efficacy of VES correlated with increased accumulation of IGFBP-3 in mouse serum as well as in the xenograft tumors and TRAMP prostate samples. Consequently, reduced proliferation and induced apoptosis were witnessed.

CONCLUSIONS:

VES mediates its therapeutic and preventive effects against prostate cancer at least partially through up-regulating IGFBP-3, which inhibits cell proliferation and promotes cell apoptosis.

PMID:
17404112
DOI:
10.1158/1078-0432.CCR-06-1217
[PubMed - indexed for MEDLINE]
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