Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 291-304
Cancer Letters

Mini-review
Multi-targeted prevention of cancer by sulforaphane

https://doi.org/10.1016/j.canlet.2008.04.018Get rights and content

Abstract

Isothiocyanates are found in cruciferous vegetables such as broccoli, Brussels sprouts, cauliflower, and cabbage. Epidemiologic studies suggest that cruciferous vegetable intake may lower overall cancer risk, including colon and prostate cancer. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and is especially high in broccoli and broccoli sprouts. SFN has proved to be an effective chemoprotective agent in cell culture, carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer. Early research focused on the “blocking activity” of SFN via Phase 2 enzyme induction, as well as inhibition of enzymes involved in carcinogen activation, but there has been growing interest in other mechanisms of chemoprotection by SFN. Recent studies suggest that SFN offers protection against tumor development during the “post-initiation” phase and mechanisms for suppression effects of SFN, including cell cycle arrest and apoptosis induction are of particular interest. In humans, a key factor in determining the efficacy of SFN as a chemoprevention agent is gaining an understanding of the metabolism, distribution and bioavailability of SFN and the factors that alter these parameters. This review discusses the established anti-cancer properties of SFN, with an emphasis on the possible chemoprevention mechanisms. The current status of SFN in human clinical trials also is included, with consideration of the chemistry, metabolism, absorption and factors influencing SFN bioavailability.

Introduction

Cancer is the second leading cause of death in the United States. With over 1.4 million people estimated to be diagnosed with cancer in 2007, preventive measures that target the various steps involved in cancer initiation and progression could significantly decrease the incidence and mortality of cancer. In particular, the use of dietary chemoprevention strategies has gained significant interest. Research investigating the use of diet-derived chemoprevention compounds may have significant impact on qualifying or changing recommendations for high-risk cancer patients and thereby increase their survival through simple dietary choices with easily accessible foods. Epidemiologic studies suggest that cruciferous vegetable intake may lower overall cancer risk, including colon and prostate cancer, particularly during the early stages [1], [2]. However, in vitro and in vivo data provide evidence that increasing cruciferous vegetable intake provides protection at every stage of cancer progression. Thus, there is growing interest in identifying the specific chemoprotective constituents in cruciferous vegetables and their mechanisms of action at all stages of cancer.

One such family of chemoprotective constituents are isothiocyanates (ITC) which are formed by hydrolysis of their precursor parent compounds glucosinolates. Within the plant, glucosinolate content can vary greatly between and within members of the Cruciferae family depending on cultivation environment and genotype [3] and there are over 120 glucosinolates in the various varieties of cruciferous vegetables, each yielding different aglycone metabolic products including isothiocyanates [4]. The general structure of glucosinolate consists of a β-d-thioglucose group, a sulfonated oxime group, and a variable side chain. Many of the anti-cancer effects observed from cruciferous vegetables have been attributed to the ITCs rather than their parent glucosinolates. Two important and well studied isothiocyanates derived from cruciferous vegetables are sulforaphane (SFN) and indole-3-carbinol (I3C). The glucosinolate precursor to SFN, glucoraphanin, is abundant in broccoli, cauliflower, cabbage, and kale with the highest concentration found in broccoli and broccoli sprouts [5]. Hydrolysis of glucoraphanin to its aglycone product SFN requires the activity of myrosinase enzymes released from the plant during consumption and other myrosinase enzymes present in our gut. The structures of glucoraphanin and SFN are shown in Fig. 1. This review will focus on SFN in cancer development. A more in-depth review of I3C is presented elsewhere [6].

The mechanisms of SFN chemoprevention have been well studied and reveal diverse responses depending upon the stage of carcinogenesis. For another comprehensive review of the possible molecular mechanisms of chemoprevention by SFN, refer to a recent review by Juge et al. [7]. SFN can function by blocking initiation via inhibiting Phase 1 enzymes that convert procarcinogens to proximate or ultimate carcinogens, and by inducing Phase 2 enzymes that detoxify carcinogens and facilitate their excretion from the body. Once cancer is initiated, SFN can act via several mechanisms that modulate cell growth and cell death signals to suppress cancer progression. Prostate and colon cancer are the first and third most prevalent cancers in men in the United States, respectively. This review will discuss overall function and metabolism of SFN, with a focus on the mechanisms for chemoprevention of prostate and colorectal cancer development and discuss its capacity to act during both initiation and post-initiation stages. In particular, this review will discuss novel targets of SFN for chemoprevention, including mechanisms of cell cycle arrest, epigenetic regulation and modulation of cell signals.

Section snippets

Molecular targets/anti-cancer properties of sulforaphane

The molecular targets of SFN vary depending upon cancer stage and target tissue. Recent work has clearly implicated multiple targets of SFN action. Since SFN was first identified in 1992 as a potential chemopreventive agent [8], there has been a sharp increase in PubMed citations mentioning SFN. Early research focused on Phase 2 enzyme induction by SFN, as well as inhibition of enzymes involved in carcinogen activation, but there has been growing interest in other mechanisms of chemoprotection

Metabolism and bioavailability

The metabolism of SFN is summarized in Fig. 3. The initial reaction involves enzymatic hydrolysis of glucoraphanin, the glucosinolate precursor of SFN, found in the plant. This reaction is catalyzed by myrosinase, a β-thioglucosidase, which cleaves the glycone from the glucosinolate forming glucose, hydrogen sulfate and one of many different aglycones (e.g. thiocyanate, ITC, or a nitrile) depending on the glucosinolate, reaction pH, and availability of ions [50]. At neutral pH, the major

Pharmacokinetics

The ability of SFN to be distributed throughout the body and reach target tissues has been investigated in vivo, in mouse models and in human subjects. In the human small intestine, SFN can be efficiently absorbed and conjugated to GSH. Human perfusion experiment showed that 74 ± 29% of SFN from broccoli extracts can be absorbed in the jejunum and that a portion of that returns to the lumen of the jejunum as SFN–GSH [14]. Pharmacokinetic studies in both rats and humans also support that SFN can

Preclinical and clinical studies

In preclinical rodent models, there is significant data supporting the chemopreventive effects of SFN at several stages of carcinogenesis. SFN supplementation administered both pre- and post-initiation decreased colonic aberrant crypt foci in azoxymethane (AOM)-induced rats. In contrast, supplementation with SFN–NAC was only effective post-initiation, suggesting different mechanisms of action between parent SFN and its metabolites [65]. SFN supplementation also decreased polyp formation in Apc

Conclusions

Cancer is a dynamic and multi-faceted disease that impacts morbidity and mortality in every country of the world. Prostate and colon cancers are highly prevalent in the US, collectively representing 18% of all cancer deaths in men. Lifestyle changes can potentially eliminate one third of these cancers, and epidemiological data indicates an inverse relationship between cruciferous vegetable intake and cancer risk. SFN has been postulated to be one of the principle ITCs found in cruciferous

Acknowledgements

Work presented here was from studies supported in part by NIH Grants CA65525 (R.H.D.), CA80176 (R.H.D.), CA90890 (R.H.D.), CA122959 (R.H.D.), CA122906 (E.H.), CA107693 (E.H.), the Oregon Agricultural Experiment Station, as well as NIEHS center Grant P30 ES00210.

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