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

anticancer 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 Figure 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 1st and 3rd 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 cell signals.

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Cancer Lett. 2008 October 8; 269(2): 291–304. doi:10.1016/j.canlet.2008.04.018