Abstract

Although the antitumor effect of alpha-tocopheryl succinate (vitamin E succinate) has been well demonstrated, its underlying mechanism remains elusive. This study provides evidence that inhibition of Bcl-xL/Bcl-2 function represents a major pathway whereby alpha-tocopheryl succinate mediates apoptosis induction in prostate cancer cells. In vitro data indicate that alpha-tocopheryl succinate was able to disrupt the binding of Bak BH3 peptide to Bcl-xL and Bcl-2 with IC50 of 26 microm, in line with its potency in antiproliferation. Treatment of PC-3 cells with this agent led to reduced association of Bcl-2 and Bcl-xL with Bak, leading to caspase-dependent apoptosis. Moreover, overexpression of Bcl-xL protected LNCaP cells from the apoptosis induction. This mechanistic finding provided a basis to develop potent Bcl-xL/Bcl-2 inhibitors. Docking of alpha-tocopheryl succinate into the Bak peptide-binding site indicates that it adopted a unique hairpin-shaped conformation for protein interactions. We rationalized that the hemisuccinate and the two proximal isopranyl units of the side chain played a crucial role in ligand anchoring and protein-ligand complex stabilization, respectively. However, exposure of the distal isopranyl unit to a polar environment might diminish the binding affinity of alpha-tocopheryl succinate. This premise was corroborated by a structure-activity analysis of a series of derivatives with truncated side chains and/or altered carboxyl terminus. This computer model predicted that the removal of the distal isopranyl unit from the side chain would improve binding affinity, leading to two agents with significantly higher potency in inhibiting Bak peptide binding and in suppressing prostate cancer cell proliferation.

Highlights

  • In this study, we obtained several lines of evidence that Bcl-xL represented a major target by which ␣-tocopheryl succinate mediated antineoplastic activities in prostate cancer cells

  • Differential Susceptibility of LNCaP and PC-3 Prostate Cancer Cell Lines to ␣-Tocopheryl Succinate—As part of our effort to understand the mode of action of ␣-tocopheryl succinate, we examined its antiproliferative effect in two human prostate cancer cell lines, LNCaP and PC-3

  • The antitumor effect of ␣-tocopheryl succinate has been the focus of many recent investigations, the underlying mechanism has not yet been fully characterized

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Summary

Introduction

We obtained several lines of evidence that Bcl-xL represented a major target by which ␣-tocopheryl succinate mediated antineoplastic activities in prostate cancer cells. This premise is supported by the inverse relationship between increased expression levels of Bcl-xL and susceptibility to the apoptosis-inducing effects of ␣-tocopheryl succinate in these three cell lines. We assessed the dose-dependent effect of ␣-tocopheryl succinate on the expression of different Bcl-2 family members in PC-3 cells, including Bcl-xL, Bcl-2, Bax, Bak, Bad, and Bid by Western blotting.

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