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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
Document code A
Article ID1672-3651(2008)05-0325-08
O
SFN
CH3-S-(CH2)4-N=C=S
AITC
CH2=CH-CH2-N=C=S
PITC
N=C=S
BITC
CH2-N=C=S
PEITC
(CH2)2-N=C=S
PPITC
(CH2)3-N=C=S
PBITC
(CH2)4-N=C=S
PPeITC
(CH2)5-N=C=S
PHITC
(CH2)6-N=C=S
fore, ITCs have been investigative hot spot spontaneously because they derive from vegetables of daily
food.
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.
Yuan Peng, et al. /Chinese Journal of Natural Medicines 2008, 6(5): 325332
Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332
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) .
Research directions
Era
Correlated researcher
2008
2007
2007
2006
TA Shapiro etc.
2004
2003
2001
2000
Jennifer H etc.
1999
1998
TA Shapiro etc.
1992
FL Chung etc.
Discussion
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
Conclusions
Procarcinogens
Induction phase
Ultimate
carcinogens
Promotion phase
Gene mutation
Progression phase
Precancerous lesion
Cancer formation
Yuan Peng, et al. /Chinese Journal of Natural Medicines, 2008, 6(5): 325332
Abbreviations
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.
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