The Therapeutic and Preventive Effect of RRR-α-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-a-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 inVES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy. Results: We found thatVES 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.

Lobe-Specific Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Mouse Model

“…Besides the effect of androgen deprivation therapy (ADT) on the progression of PCA by surgical castration of TRAMP mice [41,42], the effects of many agents with chemopreventive potential including green tea [26,43], NSAIDs [44,45], flutamide [46], retinoic acid [47], vitamin E analog [48], genistein [24,49], epigallocatechin-3-gallate (EGCG) [50], silibinin [23,51], dietary restriction [52] and immunotherapy [53,54], have been studied using this model. While most of the publications reported anti-cancer effects of their test compounds, El Touny et al showed that feeding TRAMP mice (TRAMP-FVB) with a diet containing 0.25% genistein from 12 to 20 WOA induced an aggressive progression of PCA, as evidenced by a 16% increase in the number of WD and PD prostates, coinciding with a 70% incidence of pelvic lymph node metastases as opposed to 0% in the control group [49].…”

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

“…RRR-a-vitamin E succinate (VES), one of the most effective forms of vitamin E, exhibits multiple mechanisms in cancer prevention and treatment (4 -6). We previously showed that VES can effectively prevent and reduce the growth of prostate cancer with no significant biological toxicity (6,7). The mechanisms seem to be via (a) modulation of the cell cycle, (b) inhibiting invasive ability, and (c) down-regulation of the nuclear androgen receptor (7 -9).…”

In vitro and In vivo Anticancer Effects of the Novel Vitamin E Ether Analogue RRR-α-Tocopheryloxybutyl Sulfonic Acid in Prostate Cancer

“…Several nude mouse and TRAMP mouse organs, including brain, heart, lungs, liver, kidneys, spleen, gastrointestinal tract, and testis, were collected for H&E staining to assess the drug toxicity effect. All the animal procedures were reviewed and approved by the University Committee on Animal Resources at the University of Rochester (19).…”