Selenium and Cancer

Larry C. Clark Memorial Issue: A Special Issue of Nutrition and Cancer

Leonard A. Cohen

• Publisher: Psychology Press
• Year: 2001
• Print ISBN: 9781138431263
• eBook ISBN: 9781135587314
• Topic: Psychology
• Subtopic: History & Theory in Psychology
• Index: Psychology

This special issue is devoted to the cancerchemopreventive effects of the trace element selenium. Although epidemiological and animal model studies have contributed enormously to this field, the clinical trial headed by the late Dr. Larry Clark brought to light the very real possibility that selenium compounds may serve as protective agents in populations at risk for prostate, colon, and lung cancers. For this reason, experts from various disciplines have been brought together to address the current state of the knowledge of the role of selenium as an anticancer agent. It is hoped that by bringing these various approaches together in one place, the research community, both graduate students and established investigators, can better grasp the complex nature of this field. The papers in this issue cover the entire spectrum of cancer research, ranging from clinical trials to animal model studies and molecular biology.

Multiorgan Sensitivity to Anticarcinogenesis by the Organoselenium 1,4-Phenylenebis(Methylene)Selenocyanate

Karam El-Bayoumy, C. V. Rao, and Bandaru S. Reddy

Abstract: The data in this report clearly indicate that the form (structure) in which selenium is used is the most critical determinant of success in future clinical trials. Synthetic organoselenium compounds can be tailored to achieve greater chemopreventive efficacy with minimal toxic side effects by structural modifications. We demonstrated that 1,4-phenylenebis(methylene)selenocyanate is a powerful chemopreventive agent against the development of experimental colon, mammary, lung, and oral carcinogenesis. On the basis of metabolism studies of organoselenium compounds and those reported in the literature, our working hypothesis is that aromatic selenol intermediates are important entities in cancer chemoprevention. In addition, we suggest that 1,4-phenylenebis(methylene)selenocyanate not only serves as a chemopreventive agent, but it may be valuable in preventing metastatic diseases in future studies in the clinic.

Introduction

To elucidate fully how dietary modifications can be effectively harnessed for cancer control, a stepwise approach must be taken. Toward this end, diet modifications and chemoprevention constitute valuable and plausible approaches (1–3). Thus we are searching for optimal diets and for naturally occurring agents in routinely consumed foods that may inhibit cancer development. Structural modifications of established, naturally occurring chemopreventive agents have led to synthetic agents with even greater efficacy and lower toxicity. The broadly aimed chemoprevention research program in our laboratories at the American Health Foundation uses in vitro and in vivo preclinical assays (4,5). Predictable incidences of tumors are induced by agents such as those present in tobacco products or food or, in some instances, by synthetic carcinogens to provide a yardstick for measuring chemopreventive efficacy of naturally occurring or newly developed synthetic compounds.

Knowledge gained from epidemiological studies, although sometimes ambiguous, suggests that an increased risk for certain human diseases, including cancer, is related to insufficient intake of selenium (6–8). The use of selenium in human clinical trials is limited. The late Dr. Clark, who directed the Nutritional Prevention of Cancer Projects at the Arizona Cancer Center, had focused on the beneficial health effects of increased selenium intake in humans and had conducted epidemiological studies in this area (8). A key achievement is the double-blind, randomized trial of selenium-enriched yeast in patients with nonmelanoma skin cancer that led to the unexpected discovery that selenium protects against colon, lung, and prostate cancers (9,10). The outcome of Clark’s trial stimulated the initiation of two new clinical intervention trials in three European countries (PRECISE) and in the United States (SELECT) (11).

Preclinical investigations had led to a systematic study of selenium compounds as one group of cancer-chemopreventive agents that merits further research (12). At doses well above the physiological requirement, inorganic selenium in the diet or in the drinking water protects laboratory animals against cancer of the mammary gland, colon, lung, pancreas, liver, and skin (4). Inorganic and some naturally occurring selenium containing amino acids, such as selenomethionine and selenocysteine, were equally effective chemopreventive agents and had comparable toxicity (12). Yet this toxicity inhibited further research until we introduced novel synthetic organoselenium compounds (4). The rationale for synthesizing these agents is described in detail elsewhere (4,5).

Synthetic organoselenium compounds were examined as chemopreventive agents in several animal tumor models and, in some instances, were compared with inorganic selenite (Fig. 1). Achieving optimal chemopreventive potency with lowest toxicity continues to be a primary goal in our program to develop organoselenium chemopreventive agents. This report is not meant to provide a comprehensive review of the subject but, rather, to provide basic information on the efficacy of specific organoselenium compounds in several animal tumorigenesis model systems and their potential role in preventing metastatic diseases. The metabolism and mechanisms that may underlie cancer chemoprevention, as well as future directions, are discussed.

Figure 1. Structures of selenium and sulfur chemopreventive agents.

Chemoprevention of Mammary Cancer by Organoselenium Compounds

Breast cancer, one of the major health problems, is the second most frequent cause of cancer-related deaths in women. Each year, breast cancer is diagnosed in 910,000 women worldwide and 376,000 women die from the disease (reviewed in Ref. 13). Increasingly, available molecular and biochemical tools, as adjuncts to epidemiology, have provided a better understanding of the process of cancer formation or carcinogenesis. Such understanding undoubtedly will enable us to define the cancer risk of individuals and to modulate this risk by means of agents that can alter critical steps in the carcinogenesis process. The etiology of most breast cancer remains obscure, and there are no established primary prevention strategies. Moreover, advances in therapy are limited, and alternatives need to be developed for breast cancer control. Thus began the search for synthetic or naturally occurring agents that can inhibit the neoplastic events that precede the occurrence of clinically detectable cancers. We describe here highlights of our efforts on the role of organoselenium compounds as chemopreventive agents in the breast tissue in preclinical studies.

Benzyl selenocyanate (BSC) represents the first generation of synthetic organoselenium compounds developed in our laboratory (Fig. 1). BSC inhibited dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats; its sulfur analog benzyl thiocyanate (BTC) and selenite had no effect during the initiation phase of carcinogenesis (5). The presence of selenium in BSC is necessary for its chemopreventive activity, as is evident from studies comparing BSC with its sulfur analog BTC. Further support for the requirement of selenium in cancer chemoprevention was obtained from a recent study showing that diallyl selenide is superior to diallyl sulfide in inhibiting mammary cancer induced by DMBA (14).

Although BSC was more effective and less toxic than sodium selenite, subchronic toxicity studies in rats indicated that the body weights of rats given dietary BSC or selenite were significantly lower than those in control animals, suggesting that these agents exerted a systemic toxic effect or induced avoidance of food (5). Therefore, we embarked on an effort to design more effective organoselenium compounds with minimal toxic side effects. Various structural analogs of BSC were synthesized. We found that 1,4-phenylenebis(methylene)selenocyanate (p-XSC), representing the second generation of synthetic organoselenium compounds, was markedly less toxic than BSC (5). We then assessed the efficacy of dietary p-XSC (40 ppm as selenium) against DMBA-induced mammary carcinogenesis during the initiation phase (15). Finding that p-XSC inhibited DMBA-induced mammary carcinogenesis prompted us to examine the effect of dietary p-XSC on DMBA-DNA binding in the liver and mammary glands under conditions identical to those in the bioassay. We found that dietary p-XSC inhibited total DMBA-DNA binding in the mammary glands but not in the liver (15). The most profound effect was observed 24–48 h after DMBA administration. The inhibition of binding was attributed to a reduction in the formation of the three major adducts derived from bay-region diol epoxides of DMBA (anti-diol epoxide :deoxyguanosine, syn-diol epoxide:deoxyadenosine, and anti-diol epoxide:deoxyadenosine). Although details of the mechanism are not clear, inhibition of DMBA-DNA binding in the target tissue provides a plausible explanation for the chemopreventive effects of p-XSC during the initiation phase of carcinogenesis. In a recent report, we demonstrated that p-XSC had no effect on DMBA-induced oxidative damage measured as 8-hydroxy-2′-deoxyguanosine (16). This result suggests that DMBA-induced DNA covalent modification is necessary for the initiation of mammary carcinogenesis.

In a follow-up study, we extended these earlier investigations by testing the response to lower levels of p-XSC (5, 10, and 15 ppm as selenium) when given before or after DMBA administration (17). The results clearly indicated that the chemopreventive activity was not limited to the initiation stage of carcinogenesis but was also exe...

Table of contents

• Cover
• Title Page
• In Memoriam
• Introduction
• Overview: The Late Larry C. Clark Showed the Bright Side of the Moon Element (Selenium) in a Clinical Cancer Prevention Trial
• Impact of Selenium and Cancer-Prevention Findings on the Nutrition-Health Paradigm
• Se-Methylselenocysteine: A New Compound for Chemoprevention of Breast Cancer
• Multiorgan Sensitivity to Anticarcinogenesis by the Organoselenium 1,4-Phenylenebis(Methylene)Selenocyanate
• Mechanisms of Organoselenium Compounds in Chemoprevention: Effects on Transcription Factor-DNA Binding
• Dimethyldiselenide and Methylseleninic Acid Generate Superoxide in an In Vitro Chemiluminescence Assay in the Presence of Glutathione: Implications for the Anticarcinogenic Activity of L-Selenomethionine and L-Se-Methylselenocysteine
• Molecular Mechanisms of Cancer Prevention by Selenium Compounds
• Molecular Targets for Selenium in Cancer Prevention
• Protein Kinase C as a Molecular Target for Cancer Prevention by Selenocompounds
• Antiangiogenic Activity of Selenium in Cancer Chemoprevention: Metabolite-Specific Effects
• Larry Clark’s Legacy: Randomized Controlled, Selenium-Based Prostate Cancer Chemoprevention Trials
• Announcements