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Introduction
Phytochemicals in broad terms are a synonym of plant chemicals (phyto is Greek for plant); however, in common usage
the term is more limited in scope and usually refers to plant chemicals that are bioactive and are not part of the traditional
nutrients, such as vitamins and minerals. Although these compounds are generally viewed as non-essential for normal body
functioning, an increasing number of them have been shown to possess disease-fighting activities, including anticarcinogenic
and anticancer activities[1_4]. In this review, we attempt to provide an overview of the discovery and development of
sulforaphane (SF) as a cancer chemopre-ventive phytochemical. SF was isolated from broccoli in the early 1990s in our
laboratory as an inducer of phase 2
enzymes and has since been extensively studied by numerous investigators and shows a highly promising cancer-fighting
ability[5_10].
Isolation and identification of SF
Prochaska and coworkers in the late 1980s developed a cell-culture system (known as the Prochaska assay) for the
detection of inducers of phase 2 enzymes based on the
induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) in murine hepatoma Hepa 1c1c7 cells grown in microtiter
plates[11,12]. These researchers then used the assay to screen organic solvent extracts of a broad collection of fruit and
vegetables for activities involved in the induction of phase 2 enzymes. This was an important effort because it was
recognized that the induction of phase 2 enzymes, such as NQO1 and glutathione S-transferase (GST), is an important strategy for
achieving protection against
carcinogenesis[13,14] and that consumption of fruit and vegetables reduces cancer
risk[15]. They found that many extracts exhibited significant inducer
activities, but the broccoli extract was one of the richest
sources of inducer activity[16]. In an attempt to identify the
inducer(s) in broccoli, we subjected the extracts to multiple
runs of fractionation by high performance liquid
chromatography and examined each fraction for inducer
activity using the Prochaska assay. We succeeded in
isolating a liquid substance that was responsible for more than
80% of the total inducer activity in broccoli extracts. This
substance was soon identified as SF
(1-isothiocyanato-4-(methylsulfinyl)-butane) (Table 1). Approximately 9 mg of
SF was isolated from the extracts representing 640 g fresh
broccoli florets; however, it became clear later that the actual
amount of SF in the extracts was approximately 10-fold
more[17]. Laboratory synthesis of SF provided a sufficient quantity
for evaluation in animals, and SF was shown to significantly
induce both NQO1 and GST in multiple organs of mice after
oral dosing[18]. Interestingly, a literature search revealed that
SF had already been isolated more than 30 years earlier
from hoary cress (a cruciferous weed) for its antimicrobial
activity[19,20], and a recent article reports that SF occurs in a
wide variety of plants[21]. We also became aware at this time
that SF was one of a large number of naturally occurring
isothiocyanates (ITC)[22], and several ITC had previously
been shown to inhibit carcinogenesis in animal
experiments[23].
SF analogs: relationship between structure and inducer activity
In an attempt to ascertain the structural features of SF
and in the hope of generating a more potent inducer of phase
2 enzymes, more than 40 analogs of SF were synthesized and
evaluated using the Prochaska assay (see Table 1 for
representative analogs)[18,24]. SF isolated from broccoli is chiral,
possessing the R configuration, but both R-SF and the
synthetic (R,S)-SF show identical inducer potency. Change of
the oxidation state of the sulfur atom in the methylthiol group
from sulfoxide to sulfone reduced inducer activity 4-fold,
and the sulfide analog was more than 10-fold less active.
Moreover, if the sulfoxide group was replaced with the
methylene group, the inducer activity was reduced 75-fold.
However, the sulfoxide group could be replaced with a
carbonyl group without losing any inducer activity. A change
in the number of methylene units from 4 to 5 or 3 did not
significantly affect inducer activity (results not shown), nor
did the rigidity of the methylene bridge have much effect on
inducer activity, as shown by the finding that the norbonyl
ITC were almost equally active (Table 1). Although these
findings shed new light on the importance of SF structure,
we were unable to generate a more potent inducer of phase 2
enzymes than SF. Other investigators reported that
converting the _N=C=S of SF to various dithiocarbamate
structures (-NH-CS-SR, R representing various alkyl groups) did
not generate a more potent inducer
either[25,26].
Identification of edible plants or plant extracts
as carriers of SF
Subsequent studies in our laboratory showed that SF
was derived largely, if not entirely, from glucoraphanin, a
glucosinolate (β-thioglucoside N-hydroxysulfate) (Figure 1),
and that the conversion occurred during the preparation of
broccoli extracts[17]. This is not unexpected, however,
because ITC are known to be synthesized and stored as
gluco-sinolates in plants and are released when damage to plant
tissues occurs. The conversion is catalyzed by myrosinase
(thioglucoside glucohydrolase), an enzyme that coexists with,
but is physically separated from, glucosinolates in normal
plants[22]. Glucosinolates, including glucoraphanin, which
escape the plant myrosinase, can be partially (up to 45%)
hydrolyzed in the intestinal tract because the enteric
microflora are known to possess myrosinase
activity[27_30]. How-ever, the following observations indicate that it is extremely
difficult to estimate human exposure to dietary SF: (1) our
studies revealed that SF yield in different samples of
broccoli (both frozen and fresh) sold in supermarkets might differ
by as much as 9-fold, and this difference is unrelated to their
physical appearance or whether grown under conventional
or organic conditions[17], thus, making it impossible to know
how much glucoraphanin is present in a particular vegetable
without actually measuring it; (2) different cooking
conditions are likely to exacerbate variations in SF yield, as
steaming or boiling vegetables will reduce the conversion of
glucoraphanin to SF by inactivating myrosinase and
destroying SF (SF is heat-labile)[31]; (3) certain plants including
broccoli possess epithiospecifier protein (ESP), which binds to
and converts the intermediate of glucoraphanin hydrolysis
(a thiohydroximate-O-sulfonate) to a nitrile at the expense of
SF (Figure 1), but mild heating of broccoli (60_70 °C)
inactivated ESP and preserved myrosinase and increased SF yield
3_7-fold[32]; and (4) although glucoraphanin not hydrolyzed
by vegetable myrosinase could be converted to SF
in vivo by the enzyme in the enteric microflora, the growth
condition of the microflora significantly affects the
hydrolysis[28] and glucosinolate hydrolysis in humans appears to differ by
as much as 44-fold[33].
Interestingly, our research also suggests that all
gluco-sinolates in mature broccoli might already have been
synthesized in the seeds. Thus, there was approximately 15-fold
more glucoraphanin in 3-d-old broccoli sprouts
(cv Saga) than in the florets of mature
cultiva[17]. In addition to gluco-raphanin, broccoli sprouts also contain two minor
gluco-sinolates that give rise to two ITC (erucin and iberin) that
closely resemble SF in both chemical structure and
bioactivity[18,34]. Although Faulkner and coworkers report that
glucoraphanin content in mature broccoli could be increased
10-fold by crossing broccoli cultivars with selected wild taxa
of the Brassica oleracea[35], exploitation of broccoli sprouts
may offer an advantage. Investigations have revealed that
although indole glucosinolates (4-hydroxyglucobrassin,
glucobrassicin and neoglucobrassicin) comprised 68% of the
total in mature broccoli (cv Saga), this proportion fell to
3% in the sprouts[17]. Similar results were obtained in sprouts
grown from other varieties of broccoli
seeds[36]. Hydrolysis of indole glucosinolates by myrosinase yields highly
unstable ITC that spontaneously decompose to compounds
such as indole-3-carbinol, indole-3-acetonitrile and
3,3'-diindolylmethane, which may have undesired bioactivities[37,38].
We further demonstrated that aqueous extracts of
broccoli sprouts were an excellent vehicle for delivering the
chemopreventive activity of SF. Feeding rats with broccoli
sprout extracts in which the glucosinolates either remained
intact or were fully converted to ITC resulted in marked
inhibition of mammary tumor development in
7,12-dimethylbenz(a)anthracene-treated female Sprague_Dawley
rats[17], and the chemoprevention efficacy of the extracts was
comparable to that of pure SF at similar dose
levels[39]. The anticar-cinogenic activity of glucosinolate-containing extracts
is likely to result from the conversion of the glucosinolates to
ITC in vivo, as studies have shown that intact glucoraphanin
does not possess significant chemopreventive
activity[17,34], and blocking the conversion of glucosinolates to ITC in
broccoli sprout extracts abolishes the chemopreventive activity
of the extracts[34]. The chemopreventive activity of broccoli
sprout extracts has also been demonstrated in other
studies[40,41].
Chemopreventive mechanism of SF: more than the induction of phase 2 enzymes
Activation of nuclear factor erythroid 2-related factor 2
(Nrf2) and Nrf2 target genes Although SF was isolated
from broccoli on the basis of NQO1 induction in cultured
Hepa 1c1c7 cells (the Prochaska assay), subsequent studies
have revealed that it was capable of inducing a large number
of phase 2 genes, including epoxide
hydrolase[42,43], ferritin[43], glutamate cysteine
synthetase[42_44], glutathione
peroxidase[43,45], glutathione
reductase[43,45], GST[18,42], heme
oxygenase-1[43,45,46], thioredoxin and thioredoxin
reductase[43,47,48] and UDP-glucuronosyltransferase
1A[49,50] in cultured cells or rodent tissues
in vivo. Thus, SF may significantly
streng-then cytoprotection because these genes are involved in
various aspects of cellular defense against carcinogens and
other toxicities. Extensive mechanistic studies have shown
that the Kelch-like ECH-associated protein 1
(Keap1)-Nrf2-anti-oxidant response element (ARE) signaling pathway is
primarily responsible for the coordinate response of these
genes to SF. Studies show that the phase 2 genes carry in
their 5'-flanking region one or more cis-acting DNA
regulatory elements, known as ARE, and activation of ARE leads
to coordinate induction of these
genes[51]. Nrf2 is the key ARE activator, which is normally bound by its repressor
Keap1 in the cytoplasm and targeted for proteosomal
degradation, but dissociates from the latter in response to
an inducer or other signals. Free Nrf2 translocates to the
nucleus, complexes with other nuclear factors (eg small Maf)
and binds to ARE to activate the transcription of the
downstream gene[52]. SF was shown to activate Nrf2 by directly
reacting with the sulfhydryl groups of critical cysteine
residues of Keap1[53], although a recent study found that
modifying specific cysteines of Keap1 might be insufficient for
Nrf2 activation[54] and other studies implicated the
mitogen-activated protein kinase pathway in Nrf2 activation by
SF[55,56]. Nrf2 knockout rendered phase 2 genes largely unresponsive
to SF[42,43] and two mouse studies have shown that Nrf2
knockout not only increased the susceptibility of the
animals to chemical carcinogenesis but also abolished the
ability of SF to inhibit
carcinogenesis[57,58]. Interestingly,
gene-array studies revealed that SF also upregulated a large
number of non-phase-2 genes, and the response of some of these
genes to SF also depended on the Keap1-Nrf2-ARE
pathway[42,43,59].
Modulation of cytochrome P-450 enzymes In addition
to inducing phase 2 enzymes, several studies have also
shown that SF modulates certain cytochrome P-450 (CYP)
enzymes (phase 1 enzymes). CYP enzymes are important for
normal metabolic processing of numerous endogenous and
exogenous compounds, but may also activate certain
carcinogens. For example, CYP2E1 causes the activation of
carcinogens such as
N-nitrosodimethylamine[60,61] and
CYP1A2 activates
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
(PhIP) [62]. SF was shown to inhibit the catalytic
activity of a number of CYP enzymes, including
CYP1A1,1A2, 2B1/2, 2E1 and
3A4[60,61,63_66], and to downregulate CYP3A4 in
hepatocytes[64]. However, feeding rats with SF
elevated CYP1A2 expression[65] and feeding rats with
glucoraphanin (the SF precursor) elevated CYP1A1, 1A2,
2B1/2, 2C11 and 3A1 in the lungs[67]. Hence, it remains
unclear if CYP enzymes are relevant targets in SF
chemo-prevention.
Induction of apoptosis and inhibition of proliferation
Induction of apoptosis and inhibition of proliferation are
important mechanisms for the inhibition of carcinogenesis
and cancer growth. In addition to acting as an inducer of
phase 2 genes, numerous studies have also documented the
ability of SF to induce apoptosis and cell cycle arrest in
cancer cell lines derived from
bladder[68,69], blood[70,71],
brain[72], breast[73],
colon[74,75], ovary[76],
pancreas[77], prostate[78,79] and skin[80], indicating that this activity is not cell
specific. SF also inhibited the growth of human cancer
xenografts in mice in vivo and tumor tissues of SF-treated
mice showed increased
apoptosis[77,79]. SF has been shown to activate several
programmed cell death mechanisms, including
mitochondria-mediated apoptosis[74,81], death-receptor-mediated apoptosis[82_84] and autophagic cell
death[85], and to arrest cells in G1
phase[69,78,86], S phase[68] and/or G2/M
phase[68,77,87,88], depending on the cell line under study.
Moreover, these and other studies have shown that these
actions of SF are associated with the modulation of many
regulators of cell death and cell cycle, including activation
of mitogen-activated protein kinases, modulation of Bcl-2
family proteins, damage of mitochondria and release of
apoptogenic factors from mitochondria, activation of
caspases, modulation of cyclins and cdks, downregulation
of Cdc25C, upregulation of p21, inhibition of histone
deacetylase and tubulin
polymerization[10,68,79,81,88_93]. The
anticancer activity of SF does not depend on p53 because
SF induced apoptosis in wild-type p53-, mutated p53- and
p53 knockout fibroblasts[94], induced autophagy in both
human prostate cancer PC-3 cells (p53-deficient) and LNCaP
cells (p53-normal) [85], and induced G1 arrest in human colon
cancer HT-29 cells in a p53-independent
manner[95]. SF may also potentiate other anticancer agents because it has been
shown to enhance the efficacy of doxorubicin and reverse
doxorubicin-resistant phenotype in mouse fibroblasts with
p53 mutation[96,97].
Inhibition of angiogenesis and
metastasis More recent studies demonstrate that SF is also capable of inhibiting
angiogenesis and metastasis. Using immortalized human
microvascular endothelial HMEC-1 cells, SF was shown to
potently reduce in vitro formation of microcapillaries,
suppress capillary-like tube formation on basement membrane
matrix and inhibit cell migration[98]. These effects were not
due to inhibition of cell proliferation, but were associated
with transcriptional downregulation of factors important for
tumor angiogenesis and metastasis, including vascular
endothelial growth factor (VEGF) and its receptor KDR/flk-1,
hypoxia-inducible factor-1α (Hif-1α), c-Myc and matrix
metalloproteinase (MMP)-2. SF also inhibited the
proliferation and tubular formation on matrigel of human umbilical
vein endothelial cells in
vitro[99], and was responsible for inhibition of MMP-9 activity and invasiveness of human
breast cancer MDA-MB-231 cells by broccoli
extracts[100]. Both MMP-2 and MMP-9 play an important role in cancer
cell invasion[101]. Inhibition of angiogenesis and metastasis
by SF was also demonstrated in vivo. Intravenous
administration of non-toxic doses of SF inhibited endothelial cell
response to VEGF in a subcutaneous VEGF-impregnated
matrigel plug mouse model[102]. Moreover, although
intravenous injection of B16F-10 melanoma cells into C57BL/6 mice
led to formation of lung tumor nodules, SF administered
intraperitoneally at very low dose (0.5 mg/kg body weight)
markedly inhibited lung tumor nodule
formation[103]. The potent inhibitory effect of SF observed in this model did not
appear to result from a cytotoxic effect of SF on B16F-10
cells, but was associated with inhibition of MMP activation.
Other mechanisms of SF that may also contribute to its
anticarcinogenic and anticancer activity SF treatment
significantly enhanced natural killer (NK) cell activity and
antibody-dependent cellular cytotoxicity in both normal and
Ehrlich ascites tumor-bearing mice, which was accompanied
by increased proliferation of bone marrow cells, splenocytes
and thymocytes, as well as increased production of
inter-leukin-2 and interferon-g[104]. Treatment of Raw 264.7 murine
macrophages with SF resulted in the inhibition of
lipopoly-saccharide (LPS)-induced secretion of pro-inflammatory and
procarcinogenic signaling molecules, including nitric oxide,
prostaglandin E2 and tumor necrosis
factor-α, and nuclear factor-kappa B (NF-κB) was shown to be the molecular
target of SF[105]. SF also inhibited diesel-extract-induced
production of pro-inflammation cytokins in primary human
bronchial epithelial cells[106]. Further studies in human prostate
cancer PC-3 cells showed that suppression of NF-κB and
NF-κB-regulated gene expression involved inhibition of IkB
kinases (IKK) and IκBα as well as inhibition of nuclear
translocation of p65[107].
O6-methylguanine-DNA methyltrans-ferase (MGMT) is a DNA repair protein that protects the
genome against the mutagenic action of alkylating
carcino-gens, such as
4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-one (NNK) and nitrosamines. Treatment of human
medulloblastoma UW228 cells and human colon carcinoma
HT29 cells with SF significantly increased MGMT
activity[108]. Ornithine decarboxylase (ODC) is a rate-limiting enzyme in
polyamine biosynthesis, and increased expression of ODC
is linked to tumor promotion. SF was shown to inhibit
12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC
activity in mouse epidermal ME308
cells[109]. SF was also shown to significantly induce the expression of
multidrug-resistance-associated protein 2 (MRP2) in primary hepatocytes
and Caco-2 cells[75,110], although it did not impact on MRP1
and P-glycoprotein[111]. Increased expression of MRP2 may
increase cellular protection against toxic chemicals.
More-over, the antimicrobial activity of SF has long been
recognized[20] and SF was recently shown to be effective against
Helicobacter pylori, a significant risk factor for gastric
cancer[57,112].
Preclinical and clinical evaluation of the
in vivo efficacy of SF
Preclinical A variety of rodent models have been used
to assess the in vivo efficacy of SF, some of which have
been mentioned above. SF was shown to significantly
inhibit tumor development induced by a number of chemical
carcinogens in several rodent organ sites, including
colon[113], lungs[114],
mammary[39], pancreas[115],
skin[58,116] and
stomach[57], and SF was effective when it was given either in the
carcinogen initiation phase or in the promotion phase. SF is
believed to be responsible for the inhibition of ultraviolet
(UV)-induced skin carcinogenesis by broccoli sprout extracts,
which were applied topically after the completion of UV
treatment (during the post-initiation phase)
[117]. Some of these studies also highlight the importance of phase 2 induction in
enabling the chemopreventive activity of SF, especially in
the initiation phase, as induction of phase 2 genes in target
tissues has been detected in SF-treated
animals[26,117], and knockout of Nrf2 abolished the induction of phase 2 genes
by SF and abrogated the chemopreventive activity of
SF[57,58]. However, other studies show the importance of other
chemopreventive mechanisms of SF. For example, SF
administered to A/J mice after the completion of a combined
treatment of benzo(a)pyrene and NNK inhibited malignant
progression of adenoma to adenocarcinoma in the lungs with a
corresponding increase in apoptotic cells and a decrease in
proliferating cell nuclear antigen
expression[114]. SF supplemented in the diet significantly inhibited the formation of
intestinal polyps in ApcMin/+ mice[118]. Tumors in these
mice occur spontaneously because of a mutation of the
tumor suppressor adenomatous polyposis coli (APC)
gene[119]. Analysis of polyp tissues from SF-treated mice did not
indicate induction of phase 2 genes, but instead showed
increased apoptosis and decreased proliferation. Further study
of the polyp tissues using a microarray technique showed
that SF treatment caused upregulation of multiple
pro-apoptotic genes and downregulation of multiple pro-survival
genes[120]. The anticancer activity of SF was further
demonstrated in experiments where SF dosed either orally or
intraperitoneally significantly inhibited the growth of
subcutaneous xenografts of human prostate cancer PC-3 cells and
human pancreatic cancer PANC-1 cells in
mice[77,79], and inhibited lung tumor formation from intravenous injection of
B16F-10 melanoma cells in mice[103].
Clinical To the best of our knowledge, SF in pure form
has not yet been investigated in humans. However, the
discovery of broccoli sprouts as an exceptionally rich source of
SF has provided an alternative to examine its potential
impact in humans. A placebo-controlled, double-blind,
randomized phase 1 study of broccoli sprout extracts,
containing either glucosinolate (mainly glucoraphanin) or ITC (mainly
SF), showed that the extracts were well tolerated and caused
no significant adverse effects when the extracts were
administered orally at 8-h intervals for 7 d at doses of 25 and 100
µmol glucosinolate or 25 µmol
ITC[121]. In another randomized and placebo-controlled study involving 200 healthy
adults, nightly consumption of hot water infusions of
broccoli sprouts containing 400 µmol glucoraphanin (656 µmol
total glucosinolate) for 2 weeks was also well tolerated and
showed no adverse effects[33]. Topical application of SF as
high as 340 nmol in the form of broccoli sprout extracts to the
center of a 1-cm-diameter circle of skin in humans caused no
adverse reactions, but NQO1 activity in the skin tissues was
elevated 1.5-fold and 4.5-fold after application of 150 nmol
SF once or three times, respectively, (at 24
h-intervals) [40].
Metabolism and disposition of SF
Animal and human studies Many lines of evidence
indicate that SF is rapidly metabolized through the mercapturic
acid pathway: initial conjugation with glutathione (GSH)
promoted by GST gives rise to the corresponding conjugate,
which undergoes sequential enzymatic modifications to form
cysteinylglycine, cysteine and N-acetylcysteine (NAC)
conjugates, which are disposed in urine (Figure 2).
Approximately 72% of a single oral dose of SF was recovered in the
urine as NAC conjugates in rats in 24
h[122], but only about 1% of the dose was detected in the second 24-h urine
sample[41], indicating that urinary elimination occurs almost entirely
within 24 h after SF dosing. Similar changes were seen in
humans because 58.3±2.8% and 77.9±6.4% of a single dose
of approximately 200 µmol ITC (mainly SF) contained in
broccoli sprout extracts was recovered in the urine as SF
equivalents in 8 h and 72 h, respectively, although the levels of free
SF and individual metabolite were not
determined[123]. These results also show that the bioavailability of SF is extremely
high and inter-individual variation of SF absorption and
metabolism is small. Moreover, the urinary SF elimination
pattern was not significantly altered even after repeated SF
dosing (oral broccoli sprout extracts containing 25 µmol ITC
at 8-h intervals for 7 d) [121]. The rapid urinary elimination of
SF is closely correlated with its rapid
absorption[124] and short plasma half-life because plasma concentrations of SF
equivalents peaked (0.94_2.27 µmol/L) 1 h after feeding the extracts
in the afore-described human experiment (single dose of
approximately 200 µmol ITC) and declined with first-order
kinetics (half-life 1.77±0.13 h). Similar results were seen in
other studies in which human subjects were given a single
dose of mature broccoli soup[125,126]. These studies also
revealed that free SF and its cysteine conjugate were more
abundant than the other conjugates in the plasma and that
significant quantities of free SF and cysteine conjugate were
present in the urine in addition to the NAC conjugate. It is
important to note that the thiol conjugates of SF as well as
those of other ITC serve as carriers of
ITC[127], and SF-NAC has been shown to exhibit equally if not more potent
chemopreventive activities in comparison with
SF[78,114,128,129].
Cell culture studies Studies in cultured cells in our
laboratory have provided an explanation for the rapid absorption
and elimination of SF observed in vivo. We have shown that
SF as well as other ITC are rapidly accumulated in cells, but that
the accumulated ITC equivalents are rapidly
exported[130_134] (Figure 3). ITC appear to penetrate cells by diffusion, but
the ITC upon entering the cells is rapidly conjugated with
intracellular thiols. GSH, which is the most abundant
intracellular thiol, is the major driving force for ITC accumulation,
and cellular GST enhances ITC accumulation by promoting
the conjugation reaction. Not surprisingly, ITC that are
already conjugated with thiols are unable to accumulate in
cells[131]. It has been shown that peak intracellular ITC
accumulation is achieved within 0.5_3 h after exposure, reaching
100_200-fold over the extracellular ITC concentration, and
the peak intracellular ITC accumulation levels can reach the
millimolar concentration range. However, intracellularly
accumulated GSH conjugates of ITC, perhaps other conjugates
as well, were also exported rapidly, and this appears to be
mediated at least, in part, by membrane transporter
MRP1[133,134]. For example, the half-life of the accumulated SF
equivalent in human prostate cancer LNCaP cells was only about 1
h. Thus, continuous intracellular accumulation seems to be
possible only if there is a continuous presence of ITC in the
extracellular space to allow continuous cellular uptake of
ITC to offset the rapid export of accumulated ITC conjugates.
Conclusion and future perspectives
Since SF was reported to be the principle inducer of phase
2 enzymes in broccoli in 1992, extensive studies of this
compound have followed, which reveal that SF is a highly
promising agent for cancer prevention and perhaps also useful in
cancer therapy. A summary of its cellular uptake and
molecular mechanisms is provided in Figure 3. Given the
widespread interest in SF, our understanding about its
mechanism as well as its bioactivity will undoubtedly become more
sophisticated. Broccoli sprout extracts are an excellent
vehicle for SF delivery and have allowed for human evaluation
of SF in the absence of the approved use of pure SF. In fact,
we are aware that more human trials with this substance are
either ongoing or are to be initiated in the near future. These
studies will not only address the utility of broccoli sprout
extracts for cancer prevention/treatment in humans, but will
also provide critical information as to whether the
investigation of pure SF in humans is warranted. In addition, it is
important to note that a few studies have shown the ability
of SF to enhance the efficacy of another anticancer agent.
More investigations of this ability of SF should be
emphasized to determine whether SF can be used in combination
therapy.
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