You are on page 1of 8


Journal of

Chinese Journal of Natural Medicines 2008, 6(5): 325332

Anticancer Mechanisms and Researches of Isothiocyanates

YUAN Peng1, CHEN Bao-An1*, LIU De-Long2

Department of Hematology Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, China;
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA
Available online: 20 Sep. 2008

ABSTRACT The anticancer effects of Isothiocyanates and their synthetic derivates (ITCs) are very extensive. The anticancer
mechanisms and the researches of ITCs are reviewed in this paper. The mechanisms may be combination and modification of
drug-metabolizing enzymes, influence on the cell cycle and cell differentiation, induction of apoptosis, suppression of proliferation and
angiogenesis, anti-oxidant, anti-inflammatory, immune-enhancing, anti-hormone effects, inhibition activity of Cycloxygenase-2, synergy on anticancer drugs and reverse effect on drugs resistant. ITCs are ideal chemoprevention and anticancer agents since they can
affect different phases of multistage carcinogenesis. Many related clinical researches have confirmed that ITCs have the functions of
anticancer and chemoprevention. So ITCs are not only multitarget chemoprevention agents, but also quite promising chemoprevention
and anticancer agents.
KEY WORDS Isothiocyanates; Anticancer; Mechanisms; Researches

CLC Number R96

Document code A

Article ID1672-3651(2008)05-0325-08

Isothiocyanates (ITCs) are abundant in cruciferous

vegetables. The researches of anticancer constituent
have shown that cruciferous plants have predominant
chemoprevention, with results clearly pointed toward a
positive correlation between cancer prevention of many
target organs and consumption of cruciferous vegetables or their active constituents [1]. And further studies
have shown that ITCs were major constituents of cruciferous plants with antitumor effects. ITCs is generic
name of micromolecular structure which is characteristic with -N=C=S. (Fig.1) There are more than 20
kinds of natural and synthetic derivates of ITCs, and all
of them have antitumor effect in different degrees [2].
Furthermore, there is a close relationship between different structure of ITCs and their antitumor effects.
With the development of study on morbidity and
therapeutics of cancer, we realize that ITCs are promising chemoprevention and anticancer agents. ThereReceived on 23-Jun-2008
Foundation Item This project was supported by the National
Natural Science Foundation of China (No. 39970832, 30740062)
*Corresponding authorCHEN Bao-An: Prof.Tel: 86-2583272006, E-mail:
Copyright2008, China Pharmaceutical University.
Published by Elsevier B.V. All rights reserved.



















Fig. 1 Chemical structures of some ITCs

fore, ITCs have been investigative hot spot spontaneously because they derive from vegetables of daily

1 Anticancer mechanisms and correlated researches of ITCs

1.1 Block chemical carcinogens and prevent gene
ITCs are intensive blocking agents of chemical

Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332

carcinogens. They can inhibit phaseenzyme and induce phase enzyme. Naturally occurring ITCs, such
as BITC, are potent and selective inhibitors of carcinogenesis induced by a variety of chemical carcinogens. These effects appear to be mediated through favorable modification of both phases I and II enzymes
involved in carcinogen metabolism. BITC is a mechanism-based inactivator of rat P450s 1A1, 1A2, 2B1,
and 2E1, as well as human P450s 2B6 and 2D6. This
irreversible inactivation of P450s by BITC could contribute significantly to its chemopreventive action[3].
BITC can also significantly induce GST activity in
RL34 cells, and specifically enhance the production of
the class GST isozyme (GSTP1)[4]. SFN may decrease the risk of prostate cancer through the induction
of phase II enzymes, including glutathione
S-transferases (GSTs)[5].
On molecular level, the regulation of both basal
and inducible expression of protective enzymes is mediated in part by the antioxidant response element(ARE), a cis-acting sequence found in the
5-flanking region of the genes encoding many phase II
enzymes such as mouse glutathione S-transferase (GST)
Ya, human NAD(P)H quinone oxidoreductase (NQO1),
and human -glutamylcysteine ligase[6,7]. The core sequence of the ARE has been identified as
TGACnnnGC, and several transcription factors are
known to bind to the ARE, such as nuclear factor
E2-related factor2 (Nrf2) and Nrf1.NQO1 and total
GST activities are significantly lower in Nrf2/ mice
compared with Nrf2+/+ mice[8], so Nrf2 is essential to
induction of GST and NQO1 activities in vivo[9]. Nrf2,
which is normally sequestered in the cytoplasm by
Kelch-like ECH-associated protein 1, dissociates from
Kelch-like ECH-associated protein 1 on exposure to
ARE-mediated inducers. Then, Nrf2 translocates to the
nucleus and binds to ARE[10]. Rapid and simple assays
have been devised to identify that chemical agents can
stimulate this signaling pathway. Moreover, many ARE
mediated inducers have been identified, such as ITCs,
and several of them have shown promising cancer preventive activity. A novel ITCs, such as 3MP-ITC, not
only induced endogenous Nrf2 protein, but also suppressed endogenous Keap1 protein, resulting in an increased nuclear accumulation of Nrf2[11]. So, accumulated Nrf2 is able to strongly induce Nrf2-dependent
ARE-mediated detoxifying/antioxidant enzymes in
vitro and in vivo.

In a word, ITCs are indirect antioxidants, which

have the function of eliminating intracellular oxygen
free radical. They are blocking agents of chemical carcinogens, which have a considerable effect on prevention of gene mutation.
1.2 Induction of necrosis and apoptosis, suppression
of proliferation, influence on cell differentiation
The effect of ITCs is associated with their dosage.
ITCs such as PMITC, PBITC and PHI may induce
Hela cell apoptosis on dose dependent through a caspase-3-dependent mechanism[12]. SFN can sensitize
both Bcl-xL and Bcl-2 overexpressing hepatoma cells
to TRAIL-induced apoptosis[13]. PEITC and SFN can
induce human nonsmall lung cancer A549 cells apoptosis by inhibiting downstream activation of SAPK.
And PEITC is a stronger inducer of apoptosis than
ITCs can rapidly inhibit growth of cancer cells by
modulating multiple cellular targets, and their antiproliferative activity may be unaffected by their metabolism and disposition in vivo. ITCs display a
multi-antiproliferative mechanism in HL60/S cells,
including disruption of m, induction of apoptosis,
arrestment of cell cycle progression, and induction of
cell differentiation[15]. ITCs can also inhibit cell proliferation and arrest G1- to S-phase on vascular smooth
muscle cells[16]. Devyani Chaudhuri etc.[17] first reported that the antiproliferative effects of SFN in ovarian cancer and identified the Akt pathway as a target of
SFN. E-4IB induces an immediate dose-dependent
inhibitory action on the division of HeLa cells, with the
decrease in cell proliferation[18].
1.3 Influence on the cell cycle
ITCs can increase the breakage of DNA strand and
phosphorylation of the G2/M checkpoint enforcer
Chk2, which will lead to p21 expression. Moreover,
some dietary ITCs may exert an antiproliferative effect
through activation of the G2/M DNA damage checkpoint[19]. ITCs delay the cell cycle progression of HeLa
cells at G2/M phase, leading to inhibition of cell
growth [20]. SFN induce DU145 prostate cancer cells
G2/M arrestment and apoptosis[21]. BITC can cause
human pancreatic cancer. BxPC-3 cells arrest at G2/M
phase and decline in protein levels of G2/M regulatory
proteins including cyclin-dependent kinase 1 (Cdk1),
cyclin B1 and cell division cycle 25B (Cdc25B)[22].
SFN arrests cell-cycle progression in G1 phase by a
significant down-modulation of cyclin D3[23]. And SFN
also induce early apoptosis and block cell cycle pro-

Yuan Peng, et al. /Chinese Journal of Natural Medicines 2008, 6(5): 325332

gression at G0/G1 phase which is associating with

upregulation of the expression of cyclin-dependent
kinase inhibitor p27[24]. PEITC can up-regulate the
p21WAF-1/Cip-1 and p27Kip1 and reduce the expression of cyclins D and E. As a result, phosphorylated Rb
decrease significantly and the G1- to S-phase transition
is retarded[25].
1.4 Influence on Epigenetic
ITCs can influence on Epigenetic. Melinda
C.Myzak etc.[26] have testified that ITCs were effective
HDAC inhibitors in vitro for the first time. They also
demonstrated that SFN could dose-dependently inhibit
HDAC activity, which lead to an increase in acetylated
histones, p21Cip1/Waf1 and acetylated histones bounding to the P21 promoter. SFN acts as a cancer chemopreventive agent in vivo through the inhibition of
HDAC activity[27]. PHI is a novel histone deacetylase
inhibitor, it can modulate histone methylation in leukemia cells[28]and it also can cause RPMI8226 cells
cycle arrest in G0/G1 phase and significant apoptosis.
PHI can regulate the growth of prostate cancer cells by
inhibiting the activity of HDAC and remodelling
chromatins to activate p21 for cell cycle arrest[29].
PEITC can inhibit the activity and level of histone
deacetylases (HDACs) and induce selective histone
acetylation and methylation for chromatin unfolding.
So it can prevent and inhibit malignancies of prostate
1.5 Inhibition activity of Cycloxygenase-2
It is widely accepted that Cyclooxygenase-2
(COX-2) is associated with suppressing apoptosis,
promoting tumor angiogenesis and carcinoma change
and so on. ITCs are useful COX-2 inhibitor. 6-MITC is
an effective agent to attenuate COX-2 production [31].
SFN can down-regulate the expression of COX-2 in
mouse macrophage and the inhibition effect occurs on
the transcription level[32]. SFN can also selectively inhibit NF-B activation, then inhibit COX-2[33]. According to the research of molecular biology, there are
NF-BC/EBP (CCAAT / enhancer-binding protein)
binding sites on the cis-acting element of COX-2 promoter region[34]. Among these, NFB is a reducibility
sensitive transcription factor, which is regulated by the
ratio of oxidative GSH and reductive GSH. NFB has
a reversible modified thiol group, ITCs indirectly affect
the binding between NF-B and DNA through changing the reducibility of thiol group in the nuclear.

Moreover, ITCs inhibit the transcription activity of

NF-B, but dont affect the degradation of IB (inhibitor of NF-B) and the transfer activity of NF-B[35].
1.6 Suppression of angiogenesis
ITCs can inhibit tumor angiogenesis. The PEITCmediated inhibition of angiogenic features of human
umbilical vein endothelial cells (HUVEC) in vitro is
associated with suppression of vascular endothelial
growth factor (VEGF) secretion, down-regulation of
VEGF receptor 2 protein levels, and inactivation of
prosurvival serine-threonine kinase Akt. The inhibition
of angiogenesis may be an important mechanism in
cancer chemoprevention by PEITC[36]. SFN induces a
dose-dependent decrease in the proliferative activity of
endothelial cells, which depend on cell apoptosis. It
can also inhibit tube formation on matrigel, but does
not affect MMP production. The anti-angiogenic activity of SFN can be potentially use as an anti-cancer
drug[37]. Elisabeth Bertl etc.[38] have showed the novel
antiangiogenic activities of SFN are likely to contribute
to its cancer chemopreventive and therapeutic potential.
They also have shown SFN interferes with all essential
steps of neovascularization from proangiogenic signaling and basement membrane integrity to endothelial
cell proliferation, migration, and tube formation.
1.7 Synergy on anticancer drugs and reverse effect on
drug resistance
ITCs combined with chemotherapeutics have synergy effects. E-4IB is an effective modulator of cellular
proliferation and inducer of apoptosis with potential
utility as an anticancer drug, as well as a sensitizer to
routinely used chemotherapeutic agent cisplatin (cis-Pt).
E-4IB can synergy cis-Pt to stimulate apoptosis[39].
PEITC can repress AR transcription and expression so
that it can mediate growth arrest in androgen dependent
and independent prostate cancer cells[40]. With the AR
modulation and growth attenuation, PEITC and other
ITCs may prevent and inhibit hormone sensitive and
refractory prostate cancer.
ITCs have reverse effect on drug resistance of tumor cells. Certain dietary ITCs inhibit the P-gp and the
MRP1-mediated efflux of DNM and VBL in MDR
cancer cells[41]. BITC, PEITC, and 1-NITC inhibit the
P-gp and MRP1-mediated efflux of DNM, and GSH
acts as a cosubstrate for DNM efflux via MRP1[42].
Some ITCs are potential inhibitors of BCRP ATPase
and PEITC is transported by BCRP in its unchanged
form[43,44]. PEITC is BCRP inhibitor which is mediated

Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332

by MRP2 but not P-gp, and GSH plays an important

role in the MRP2-mediated transport of PEITC [45].
SFN can reverse the resistance to doxorubicin. The
association of SFNdoxorubicin may therefore allow
doxorubicin to be administered at lower doses, thereby
reducing its potential toxicity.[46]
1.8 Other effects: such as regulation of host immune
response and anti-inflammatory
AITC and PITC can stimulate BALB/c mouse
immunological response[47]. SFN can significantly enhance activity of natural killer (NK) cell, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement-mediated cytotoxicity
(ACC), the production of Interleukin-2 and Interferon-[48]. It can significantly enhance the proliferation
of splenocytes, bone marrow cells and thymocytes.
And it can also effectively inhibit the spread of metastatic tumor cells through the stimulation of cell-mediated immune response, upregulation of IL-2 and IFNgamma, and downregulation of proinflammatory cytokines IL-1beta, IL-6, TNF-alpha, and GM-CSF[49].
ITCs have a potent antibacterial effect against H.
pylori and are novel therapeutic agents for H. pylori
eradication[50]. Thus they can inhibit occurrence of gastric cancer.

Anticancer related clinical studies of ITCs

In recent years, cancer prevention by ITCs has received a considerable attention. The potential protective role of ITCs has been extensively studied in experimental in vitro and in vivo carcinogenesis models.
ITCs influence carcinogenesis during initiation and
promotion phases of cancer development. Cruciferous
vegetable intake consistent with high ITCs exposure
may reduce prostate cancer[51], breast cancer[52], especially among Chinese women[53]. Cruciferous vegetable
intake also may ameliorate the effects of the GSTP1
genotype[54]. The association between urinary total ITC
level and colorectal cancer risk was examined in a cohort of 18,244 men in Shanghai, China, with 16 years
of follow-up. And the present study suggests that dietary ITCs may exert tumor inhibitory effects, especially
during earlier stages of the multistage process of carcinogenesis[55]. Liyun Xiao etc.[56] have showed that the
effect of PHI on the leukemia cells from patients was
time and dose dependent. There was a significant increase of PHI effect on leukemia cells versus
non-leukemia cells (p<0.05), suggesting that PHI may
have preferential activity against leukemia cells. And
there still have many other ongoing clinical studies
(Table 1) .

Table 1 Partly clinical studies of ITCs to date (phases I and II trials)

Research directions


Correlated researcher

Urinary Total Isothiocyanates and Colorectal Cancer:

A Prospective Study of Men in Shanghai, China


Kristin A. Moy etc

Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast


Brian S. Cornblatt etc.

The Epigenetic Effect of Phenylhexyl Isothiocyanate on Histone Acetylation

in Patients with Acute Leukemia and Non-Leukemic Disorders


Liyun Xiao etc.

A clinical phase I study of broccoli sprout glucosinolates and isothiocyanates:


TA Shapiro etc.

Hydrolysis of Glucosinolates to Isothiocyanates


Gabrielle Rouzaud etc.

Urinary Isothiocyanate Levels, Brassica, and Human Breast Cancer


Jay H. Fowke etc.

Metabolism and Excretion


Theresa A. Shapiro etc.

Fruit and Vegetable Intakes and Prostate Cancer Risk


Jennifer H etc.

Effects of Watercress Consumption on Urinary Metabolites of Nicotine in Smokers


Stephen S. Hecht etc.

Human metabolism and excretion of cruciferous vegetables


TA Shapiro etc.

Quantitation of human uptake after a watercress meal


FL Chung etc.


With continuous struggle against cancer for many

years, researchers have turned anticancer focal point
from treating tumor to preventing it. Chemoprevention
is promising for mankind to conquer and control cancer.
Cancer chemoprevention encompasses the concepts of
inhibition, reversal, and retardation of the cancer process. We must attack multiple key pathways at once for

a predetermined period of time. Thus, agent combination prevention strategies are essential to decrease cancer morbidity[57]. Modern anticancer concept is target
and control. Chemoprevention agent can be divided
into three kinds, including antiinitiator, antipromoter,
antiprogressor[58]. Therefore, ideal chemoprevention
agents should include these three chemopreventive
mechanisms. Unfortunately, there are few agents in-

Yuan Peng, et al. /Chinese Journal of Natural Medicines 2008, 6(5): 325332

cluding all of these mechanisms.

However, ITCs are ideal chemoprevention agents
since they include all of these mechanisms and can
affect different phase of multistage carcinogenesis. As
showed before, firstly, ITCs are excellent blockers of
carcinogen. They can inhibit cytochrome P450 to block
activation carcinogen and induce phase detoxification enzyme inhibiting activation of electrophile. So
they can stop initiation of tumor. Secondly, ITCs are
good inhibitors of carcinomatous change. They can
induce cell differentiation, suppress signal pathway of
cellular proliferation, inhibit COX-2, influence on epigenetic of tumor cells and have antihormones effects.
So they have antipromoter effect of cancer. Last but not
the least, ITCs are fine antiprogressor. They can cause
necrobiosis and apoptosis, arrest cell cycle, synergy
antitumor and inhibit angiogenesis. (Fig. 2) Elevating immunity and reversing multidrug resistance are
also contribute to prevention and antitumor effects of
Furthermore, above-mentioned prevention and antitumor effects of ITCs are not isolated. For instance,
after inhibiting NF-B, the production of COX-2 IS

decreased, so they can influence proliferation, induce

apoptosis and suppress angiogenesis. After inhibiting
COX-2, prostaglandin synthesis decrease, so they can
inhibit release of mediators of inflammation. After inhibiting COX-2, they also can indirectly reverse multidrug resistance of acute myeloid leukaemia. For another example, among the inhibitors of DNA methylation and histone acetylation of Epigenetic, ITCs can
suppress cancer cells proliferation and induce differentiation and apoptosis. HDACI can also synergy the
effects of other anticancer drugs.


ITCs, mostly natural compounds, are efficient

cancer chemopreventive agents. The mechanisms may
be combinations of different anticancer mechanisms.
Accordingly, ITCs are suitable for application to humans because of their mild mechanisms[59]. They mediate differential reduction-oxidation signaling mechanisms with cytoprotection of normal cells versus cytotoxicity in tumor cells[60]. It is evident that ITCs are
multitarget chemoprevention agents. They are very
promising chemoprevention and anticancer agents.


Induction phase


Inhibit P450 to block activation carcinogen and

induce the expression of phase detoxification
enzyme inhibiting activation of electrophile.

Promotion phase

Gene mutation

Progression phase

Precancerous lesion

Induce cell differentiation, suppress signal pathway of

cellular proliferation, inhibit COX-2, influence on
epigenetic of tumor cells and have antihormones

Cancer formation phase.


Cancer formation

Cause necrobiosis and apoptosis, arrest cell cycle,

synergy antitumor and inhibit angiogenesis.

Fig. 2 ITCs affect different phase of multistage in carcinogenesis

Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332

ITCs, Isothiocyanates; GST, Glutathione-S-transfering enzyme; BITC, Benzyl Isothiocyanate; SFN,
Sulforaphane; E-4IB, Ethyl 4-isothiocyanatobutanoate;
PMITC, phenylmethyl isocyanate; PBITC, 4-phenylbutyl isothiocyanate; PHI, 6-Phenylhexyl isothiocyanate; AITC, allylisothiocyanate; ERN, erucin; IBN,
iberin; PETIC, phenethyl isothiocyanate; 6-MITC, 6(methylsulfinyl) hexyl isothiocyanate; 3MP-ITC, 3morpholinoproply isothiocyanate; 1-NITC, alphanaphthyl isothiocyanate; PETICNAC, PETIC- N-Acetylcysteine; P-gp, P-glycoprotein; MRP, multidrugassociated protein; BCRP, breast cancer resistance protein.


Murillo G, Mehta RG. Cruciferous vegetables and cancer

prevention [J]. Nutr Cancer, 2001, 41(1-2): 17-28.


Fahey JW, Zalcmann AT, Talalay P. The chemical diversity

and distribution of glucosinolates and isothiocyanates among
plants [J].Phytochemistry, 2001, 56(1): 5-51.


Nakamura Y, Ohigashi H, Masuda S, et al. Redox regulation

[12] Yu R, Mandlekar S, harvey KJ, et al. Chemopreventive
isothiocyanates induce apoptosis and caspase-3-like protease
activity [J]. Cancer Res, 1998, 58(3): 402-408.
[13] Kim H, Kim,EH, EomYW, et al. Sulforaphane sensitizes




(TRAIL)resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen speciesmediated up-regulation of DR5 [J]. Cancer Res, 2006, 66: 1740-1750.
[14] Mi L, Wang X, Govind S, et al. The Role of protein binding
in induction of apoptosis by phenethyl isothiocyanate and
sulforaphane in human nonsmall lung cancer cells [J].
Cancer Res, 2007, 67(13): 6409-6416.
[15] Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells [J]. Mol Cancer
Ther, 2003, 2(10): 1045-1052.
[16] Suh SJ, Moon SK, Kim CH. Raphanus sativus and its

pharmacol, 2006, 6(5): 854-861.

[17] Chaudhuri D, Orsulic S, Ashok BT. Antipro- liferative activity of sulforaphane in Akt-overexpressing ovarian cancer
cells [J]. Mol Cancer Ther, 2007, 6(1): 334345.
[18] Horakova K, Jantova S, Stred'ansky M, et al. Ethyl 4-

reactive oxygen intermediates [J]. Cancer Res, 2000, 60(2):

isothiocyanatobutanoate-antiproliferative activity in vitro

Joseph MA, Moysich KB, Freudenheim JL, et al. Crucifer-

and in vivo [J]. Anticancer Drugs, 1993, 4(3): 369-375.

[19] Visanji JM, Duthie SJ, Pirie L, et al. Dietary Isothiocyanates
Inhibit Caco-2 cell proliferation and induce G2/M phase

S-transferases M1 and T1, and prostate cancer risk [J]. Nutr

cell cycle arrest, DNA damage, and G2/M

Cancer, 2004, 50(2): 206-213.

vation [J]. J Nutr, 2004, 134(11): 3121-3126.

Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf het-

checkpoint acti-

[20] Hasegawa T, Nishino H, Iwashima A. Isothiocyanates inhibit

erodimer mediates the induction of phase II detoxifying en-

cell cycle progression of HeLa cells at G2/M phase [J].

zyme genes through antioxidant response elements [J]. Bio-

Anticancer Drugs, 1993, 4(2): 273-279.

chem Biophys Res Gommun, 1997, 236(2): 313-322.

[21] Cho SD, Li G, Hu H, et al. Involvement of c-Jun N-terminal

Kwak MK, Itoh K, Yamamoto M, et al. Enhanced expression

kinase in G2/M

of the transcription factor Nrf2 by cancer chemopreventive

duced by sulforaphane in DU145 prostate cancer cells [J].

Agents: Role of antioxidant response element-like sequences

in the nrf2 promoter [J]. Mol Cell Biol, 2002, 22(9): 2883-


oxidant enzymes in vitro and in vivo[J]. Carcinogenesis,

anate: Correlation of enzyme induction with the formation of

ous vegetables, genetic polymorphisms in glutathione


ment (ARE)-dependent Nrf2-mediated detoxifying/anti-

eration and induce G(1) cell cycle arrest [J]. Int Immuno-



cyanate that strongly induces the antioxidant response ele-

isothiocyanates inhibit vascular smooth muscle cells prolif-

of glutathione S-transferase induction by benzyl isothiocy-


ply isothiocyanate (3MP-ITC) is a novel synthetic isothio-

isothiocyanate on rat and human cytochromes P450: IdentiExp Ther, 2001, 296: 198-206.


Cancer Ther, 2004, 3(7): 885 - 893.

[11] Keum YS, Chang PP-J, Kwon KH, et al. 3-morpholinopro-

Goosen TC, Mills DE, Hollenberg PF. Effects of benzyl

fication of metabolites formed by P450 2B1[J]. Pharmacol


Stimulation of the Nrf2-ARE signaling pathway [J]. Mol

arrest and caspase-mediated apoptosis in-

Nutr Cancer, 2005, 52(2): 213-224.

[22] Srivastava SK, Singh SV. Cell cycle arrest, apoptosis induc-


tion and inhibition of nuclear factor kappa B activation in

Cho HY, Jedlicka AE, Reddy SP, et al. Role of NRF2 in pro-

anti-proliferative activity of benzyl isothiocyanate against

tection against hyperoxic lung injury in mice [J]. Respir Cell

Mol Biol, 2002, 26(2): 175-182.

human pancreatic cancer cells [J]. Carcinogenesis, 2004,

Kwak MK, Itoh K, Yamamoto M, et al. Role of transcription

[23] Fimognari C, Nusse M, Berti F, et al. Sulforaphane modu-

factor Nrf2 in the induction of hepatic phase 2 and antioxi-

lates cell cycle and apoptosis in transformed and non-trans-

dative enzymes in vivo by the cancer chemoprotective agent,

formed human T lymphocytes [J]. N Y Acad Sci, 2003, 1010:

3H-1, 2-dimethiole-3-thione[J]. Mol Med, 2001, 7(2): 135145.

[10] Zhang Y, Gordon GB. A strategy for cancer prevention:

25(9): 1701-1709.

[24] Shan Y, Sun C, Zhao X, et al. Effect of sulforaphane on cell
growth, G(0)/G(1) phase cell progression and apoptosis in

Yuan Peng, et al. /Chinese Journal of Natural Medicines 2008, 6(5): 325332
human bladder cancer T24 cells [J]. Int J Oncol, 2006, 29(4):
[25] Chiao JW, Wu H, Ramaswamy G, et al. Ingestion of an

and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention [J]. Mol Cancer Ther,
2006, 5(3): 575-585.

isothiocyanate metabolite from cruciferous vegetables inhib-

[39] Bodo J, Chovancova J, Hunakova L, et al. Enhanced sensi-

its growth of human prostate cancer cell xenografts by

tivity of human ovarian carcinoma cell lines A2780 and

apoptosis and cell cycle arrest [J]. AACR Meeting Abstracts,

A2780/CP to the combination of cisplatin and synthetic

2004, 25(8): 1403-1408.

[26] Myzak MC, Karplus PA, Chung FL, et al. A novel mechanism of chemoprotection by sulforaphane: Inhibition of histone deacetylase [J]. Cancer Res, 2004, 64(16): 5767-5774.
[27] Myzak MC, Tong P, Dashwood WM, et al. Sulforaphane re-

isothiocyanate ethyl 4-isothiocyanatobutanoate[J]. Neoplasma, 2005, 52(6): 510-516.

[40] Wang LG, Liu XM, Chiao JW. Repression of androgen receptor in prostate cancer cells by phenethyl isothiocyanate
[J]. Carcinogenesis, 2006, 27(10): 2124-2132.

tards the growth of human PC-3 xenografts and inhibits

[41] Tseng E, Kamath A, Morris ME. Effect of organic isothio-

HDAC activity in human subjects [J]. Subjects Exp Biol Med,

cyanates on the P-glycoprotein- and MRP1-mediated trans-

2007, 232(2): 227-234.

port of daunomycin and vinblastine [J]. Pharm Res, 2002,

[28] Lu LL, Ma XD, Becklemisheva A, et al. Phenolhexyl

19(10): 1509-1515.

isothiocyanate, a new histone deacetylase inhibitor, can pre-

[42] Hu K, Morris ME. Effects of benzyl-, phenethyl-, and al-

vent tumor formation and inhibit leukemia cell growth in

pha-naphthyl isothiocyanates on P-glycoprotein- and MRP1-

vivo [J]. Blood (ASH Annual Meeting Abstracts), 2005, 106:

[29] Beklemisheva AA, Fang Y, Feng J, Ma X, et al. Epigenetic
mechanism of growth inhibition induced by phenylhexyl
isothiocyanate in prostate cancer cells [J]. Anticancer Res,
2006, 26(2A): 1225-1230.
[30] Wang LG, Beklemisheva A, Liu XM, et al. Dual action on

mediated transport [J]. Pharm Sci, 2004, 93(7): 1901-1911.

[43] Ji Y, Morris ME. Membrane transport of dietary phenethyl
isothiocyanate by ABCG2 (breast cancer resistance protein)
[J]. Mol Pharm, 2005, 2(5): 414-419.
[44] Ji Y, Morris ME. Effect of organic isothiocyanates on breast
cancer resistance protein (ABCG2)-mediated transport [J].
Pharm Res, 2004, 21(12): 2261-2269.

promoter demethylation and chromatin by an isothiocyanate

[45] Y Ji, Morris ME. Transport of dietary phenethyl isothiocy-

restored GSTP1 silenced in prostate cancer [J]. Mol Car-

anate is mediated by multidrug resistance protein 2 but not

cinog, 2007, 46(1): 24-31.

P-glycoprotein [J]. Biochem Pharmacol, 2005, 70(4):

[31] Uto T, Fujii M, Hou DX. Inhibition of lipopolysac-


chride-induced cyclooxygenase-2 transcription by 6-(methyl-

[46] Fimognari C, Lenzi M, Sciuscio D, et al. Combination of

sulfinyl) hexyl isothiocyanate, a chemopreventive compound

doxorubicin and sulforaphane for reversing doxorubi-

from Wasabia japonica (Miq.) Matsumura, in mouse

cin-resistant phenotype in mouse fibroblasts with p53Ser220

macrophages [J]. Biochem Pharmacol, 2005, 70(12):

mutation [J], Ann NY Acad Sci, 2007, 1095: 6269.

[47] Manesh C, Kuttan G. Effect of naturally occurring isothiocyanates on the immune system [J]. Immunopharmacol Im-

[32] Heiss K, Herhaus C, Klimo K, et al. Nuclear factor B is
amolecular target for sulforaphane-mediated anti- infammatory mechanisms [J]. Biol Chem, 2001, 276(34): 3200832015.

munotoxicol, 2003, 25(3): 451-459.

[48] Thejass P, Kuttan G. Augmentation of natural killer cell and
antibody-dependent cellular cytotoxicity in BALB/c mice by

[33] Kim SJ, Kang SY, Shin HH, et al. Sulforaphane inhibits os-

sulforaphane, a naturally occurring isothiocyanate from

teoclastogenesis by inhibiting nuclear factor-kappa B [J].

broccoli through enhanced production of cytokines IL-2 and

Mol Cells, 2005, 20(3): 364-370.

IFN-gamma [J]. Immunopharmacol Immunotoxicol, 2006,

[34] Wadleigh DJ, Reddy ST, Kopp E, et al. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated
RAW 264.7 macrophages[J]. Biol Chem, 2000, 275(9):
[35] Hiramoto M, Shimizu N, Sugimoto K, et al. Nuclear targeted
suppression of NF-kappa B activity by the novel quinone derivative E3330 [J]. J Immunol, 1998, 160(2): 810-819.
[36] Xiao D, Singh SV. Phenethyl isothiocyanate inhibits angiogenesis in vitro and ex vivo [J]. Cancer Res, 2007, 67(5):
[37] Asakage M, Tsuno NH, Kitayama J, et al. Sulforaphane in-

28(3): 443-457.
[49] Thejass P; Kuttan G . Modulation of cell-mediated immune
response in B16F-10 melanoma-induced metastatic tumor-bearing C57BL/6 mice by sulforaphane [J]. Immunopharmacol Immunotoxicol, 2007, 29(2): 173-186.
[50] Haristoy X, Fahey JW, Scholtus I, et al. Evaluation of the
antimicrobial effects of several isothiocyanates on Helicobacter pylori [J]. Planta Med, 2005, 71(4): 326-330.
[51] Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk [J]. Natl Cancer Inst, 2000;
92(1): 61-68.

duces inhibition of human umbilical vein endothelial cells

[52] Cornblatt BS, Ye L, Dinkova- Kostova AT, et al. Preclinical

proliferation by apoptosis [J]. Angiogenesis, 2006, 9(2):

and clinical evaluation of sulforaphane for chemoprevention

[38] Bertl E, Bartsch H, Gerhuser C. Inhibition of angiogenesis

in the breast [J]. Carcinogenesis, 2007, 28(7): 1485-1490.

[53] Fowke JH, Chung FL, Jin F, et al. Urinary isothiocyanate

Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332
levels, brassica, and human breast cancer [J]. Cancer Res,
2003, 63(14): 3980-3986.
[54] Lee SA, Fowke JH, Lu W, et al. Cruciferous vegetables, the
GSTP1 Ile105Val genetic polymorphism, and breast cancer
risk [J]. Clin Nutr, 2008, 87(3): 753-760.
[55] Moy KA, Yuan JM, Chung FL, et al. Urinary total isothio-

[57] Steele VE. Current mechanistic approaches to the chemoprevention of cancer [J]. Biochem Mol Biol, 2003, 36(1):
[58] Lippman SM, Benner SE, Hong WK. Cancer chemoprevention[J]. J Clin Oncol, 1994, 12(4): 851-873.
[59] Tsuda H, Ohshima Y, Nomoto H, et al. Cancer prevention by

cyanates and colorectal cancer: a prospective study of men in

natural compounds [J]. Drug Metab Pharmacokinet, 2004,

shanghai, China [J]. Cancer Epidemiol Biomarkers Prev,

19(4): 245-263.

2008, 17(6): 1354-1359.

[60] Nair S, Li W, Kong AN. Natural dietary anti-cancer chemo-

[56] Xiao LY, Ma XD, Huang YQ, et al. The epigenetic effect of

preventive compounds: redox-mediated differential signaling

phenylhexyl isothiocyanate on histone acetylation in patients

mechanisms in cytoprotection of normal cells versus cyto-

with acute leukemia and non-leukemic disorders [J]. Blood

toxicity in tumor cells [J]. Acta Pharmacol Sin, 2007, 28(4):

(ASH Annual Meeting Abstracts), 2007, 110: 4145.