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Vitamin E Analogs as Anticancer Agents

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Jiri Neuzil, Xiu-Fang Wang, Yan Zhao, and Kun Wu

CONTENTS

Abstract.............................................................................................................111

1. 1 Introduction..............................................................................................112
2. 2 Vitamin E as an Anticancer Agent — More than an Antioxidant?........113
3. 3 Vitamin E Analogs — The Importance of Redox-Silence.....................116
4. 3.1 Structure-Function Relationship.................................................116
5. 3.2 Vitamin E Analogs as Anticancer Agents...................................120
6. 3.3 Selectivity of VE Analogs Increases Their Clinical Application..................................................................................122
7. 3.4 VE Analogs Overcome Resistance of Mutant Cancer Cells to Apoptosis, Induce the Mitochondrial Apoptotic Pathway, and Cooperate with Immunological Apoptogens.......................123
8. 3.5 Vitamin E Analogs as Antitumor Agents: Beyond Mitochondria................................................................................126
9. 3.6 Pharmacokinetics of VE Analogs — A Potential Secondary Beneficial Bioactivity..................................................................127
10. 4 Conclusions and Future Directions.........................................................128
11. .......................................................................................................129

Abstract

Numerous attempts have been made to find antineoplastic dietary supplements. Of the potential food additives, vitamin E (VE) has been a focus of significant research because there are data suggesting its potential effect against cancer, based on the ability of VE to scavenge reactive oxygen species. Although several studies indicated an inverse correlation between VE intake and incidence of cancer, the data are not convincing. As with other epidemiological studies, there has been little outcome, offering no conclusive evidence. On the other hand, recent years have witnessed emergence of novel anticancer agents from the group of VE analogs, epitomized by a-tocopheryl succinate (a-TOS). These agents, unlike VE itself, are redox-silent and, unlike VE, induce apoptosis. Additional data suggest selectivity for malignant cells and their superiority over VE in cancer suppression, at least in preclinical settings. In this chapter, we review the current status of VE and, in particular, its analogs as potential antineoplastic agents and try to suggest future directions so that some of these compounds may prove useful for treatment of multiple malignancies.

6.1 INTRODUCTION

Significant efforts have been made to find cures against diseases, of which cancer is, disputably, the greatest challenge. The problem with neoplasia is that the pathology is of clonal origin; therefore, cancer cells are undergoing chromosomal instability and frequent mutations that complicate treatment. Another complication is that many of the established anticancer drugs are nonselective, causing damage not only to the target malignant cells, but also to normal cells and tissues, compromising the treatment outcome.

Focus has been given to dietary supplements as potential anticancer drugs. Thus, agents present in the diet are, generally, nontoxic, so that they may be selective antineoplastic agents, depending on their activities. Of dietary components, vitamin E (VE) has been studied because it is capable of scavenging reactive oxygen species (ROS) that have been implicated in tumorigenesis. Many epidemiological studies have aimed at determining whether dietary VE may inhibit cancer initiation and progression. Despite these investigations, little or no correlation between VE intake and the incidence of a particular neoplastic disease has been found.

Figure 6.1 shows the structure of the biologically most active VE, a-toco-pherol (a-TOH) and its analog a-tocopheryl succinate (a-TOS), a redox-silent VE analog with strong anticancer activity.1 There are three major domains in the structure of the compounds. Domain I (hydrophobic domain) is essential for association of the agents with membranes and lipoproteins; Domain II (signaling domain) is involved in fine-tuning of the activity of the compounds; and finally, Domain III (functional domain) endows the compounds with their overall activity. Thus, the hydroxyl group gives a-TOH its redox activity, while succinate provides a-TOS with its proapoptotic activity. It is now clear that it is the chemistry of the compounds that decide their major biological activity.

Several papers reported superiority of a-TOS over a-TOH in its anticancer effect.1 This follows from studies mostly using athymic mice with human cancer xenografts. The high anticancer index of a-TOS is linked to its apoptogenic activity. This is a highly intriguing molecule because it not only suppresses cancer by causing apoptosis in malignant cells, but it also inhibits their proliferation and modulates expression of several important genes. Data are now suggesting also an antiangiogenic activity of a-TOS. Importantly, a-TOS is nontoxic to normal cells and tissues.

These notions stipulate that VE analogs hold a promise as selective anticancer agents with clinical use. At present the molecular mechanisms of their activities that translate into their antineoplastic effects are not understood in detail. It is