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

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.

• Authors: Yi Yin, Jing Ni, Ming Chen, Matthew A DiMaggio, Yinglu Guo, Shuyuan Yeh
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 7 Pg. 2271-80 (Apr 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17404112 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Insulin-Like Growth Factor Binding Protein 3
• RNA, Messenger
• RNA, Small Interfering
• Vitamin E
• Tocopherols

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunohistochemistry
• Insulin-Like Growth Factor Binding Protein 3 (drug effects, metabolism)
• Male
• Mice
• Mice, Nude
• Mice, Transgenic
• Prostatic Neoplasms (drug therapy)
• RNA, Messenger (analysis)
• RNA, Small Interfering
• Reverse Transcriptase Polymerase Chain Reaction
• Tocopherols
• Vitamin E (analogs & derivatives, pharmacology)