Extract
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Introduction
Oriental herbal medicine has been used since ancient times
to treat malignancies in China and other Asian countries.
Although some scientific evidence exists regarding a few
herbal therapies, for most herbal remedies and formulas the
key questions for Western medical providers are quality
control/assurance issues for the herbal products, their safety
and efficacy and adverse interactions with other medications.
Systematic characterization of active phytochemicals in
medicinal herbs and their mechanisms of action are
important for providing the rationale for their efficacy and for
transforming herbal practices into evidence-based medicine. This
review focuses on our discovery of decursin and its
naturally occurring pyranocoumarin analogs from an Oriental
herbal formula containing Korean Angelica
gigas Nakai (Dang Gui) root as a novel class of anti-androgen and
androgen receptor (AR) signaling agents with excellent potential
for prostate cancer (PCa) chemoprevention.
Androgen receptor and signaling as an impor-tant target for prostate cancer
chemopre-vention
Androgen and AR-mediated signaling are crucial for the
development and function of the normal prostate as well as
for PCa[1,2]. The importance of androgen in PCa is supported
by the observations that PCa rarely occurs in eunuchs or in
men with a deficiency in 5α-reductases, the enzymes that
convert testosterone to its active metabolite
5α-dihydrotes-testerone (DHT)[1]. Androgen/hormonal-ablation therapies
are standard treatments for invasive metastatic PCa because
a large percentage of the cancer cells are still responsive to
androgen. In hormone-refractory cancer that inevitably arises
after hormonal ablation therapy, which almost always brings
about 3_5 years of remission, most of the PCa cells still
retain wild-type AR. The AR is a ligand-dependent
transcrip-tion factor, mediating the genomic effects of androgen
action in the prostate and PCa cells. Novel approaches
using an anti-AR ribozyme and inactivating monoclonal
antibodies to reduce AR
protein/function[3,4] and a decoy oligonucleotide containing an androgen-responsive element
to sequester endogenous AR[5] have been developed. The
data support the critical role of AR in PCa cell survival and
proliferation in even the androgen-independent stage. More
recent work using siRNA to knockdown AR further confirms
these findings[6]. Therefore, agents that suppress AR
abundance and ligand-dependent and ligand-independent
signaling will be especially attractive for chemoprevention and
therapy of PCa.
A clinical trial with finasteride (Proscar), which inhibits
5α-reductase II within the prostate gland, has shown a
significant reduction in total PCa
incidence[7]. However, PCa that developed in subjects in the intervention group appeared
to be more advanced in tumor stages than that in the
placebo group, raising doubts about the overall survival
benefit of this single-target approach. Novel agents that target
multiple aspects of androgen and AR signaling will be more
desirable.
Screening biomarkers for
activity-guidedfrac-tionation of novel anti-AR agents
With respect to biomarkers of androgen and AR signaling,
prostate specific antigen (PSA) is a gene tightly regulated
by androgen in normal prostate and some PCa
cells[8]. A member of the kallikrein family
(KLN3), PSA is a serine protease with highly prostate-specific expression and is elevated
in the blood circulation of patients with PCa. Circulating
PSA is widely used clinically as a marker for PCa screening
and is particularly useful as an indicator of PCa response to
therapy and recurrence[8]. The LNCaP human PCa cells are
perhaps the best studied in vitro model for androgen and
AR signaling in PCa. They possess a high-affinity mutant
AR and produce high levels of PSA, which is extremely
responsive to androgen
stimulation[9,10]. In addition to PSA expression, another known outcome of androgen
deprivation or blockage of AR signaling in these cells is the
induction of neurite-like projections that have been termed
"neuroendocrine differentiation"
(NED)[11,12]. Androgen signaling represses these morphological manifestations and the
associated molecular markers such as neuron-specific
enolase[11]. Therefore, we chose this cell line as the primary cell
target for screening novel anti-androgen and AR agents
using PSA and NED as key functional biomarkers.
Our starting material was the ethanol extract of a
traditional formula, Ka-mi-kae-kyuk-tang (KMKKT; see
composition in Table 1). We have shown recently that it possesses
broad-spectra in vivo anti-cancer activities of targeting
angiogenesis, apoptosis and metastasis without any adverse
effect on body weight[13].
Findings with KMKKT and AGN extracts in terms of PSA suppression and growth
inhibi-tion activities[14]
Using the LNCaP cell model, we found that KMKKT
ethanol extract suppressed the expression of PSA mRNA and
protein (IC50 ~7 µg/mL, 48 h exposure), inhibited
androgen-induced cell proliferation and blocked the ability of
androgen to suppress NED at exposure concentrations that caused
G1 arrest, but far below doses that cause
apoptosis. Mechanistically, KMKKT extract inhibited
androgen-stimulated AR translocation to the nucleus and downregulated
AR protein abundance without affecting the AR mRNA
level. To identify the herb(s) containing anti-androgen activities,
we prepared an ethanol extract of each of the 10
herbs. The AGN extract exerted a concentration-dependent suppression
of cellular PSA and the IC50 for AGN extract was estimated to
be ~1 µg/mL[14]. As decursin is a known major component of
Korean AGN[15_17], which we confirmed using TLC and HPLC
analyses[14], we focused on this phytochemical (structure
shown in Figure 1) as a likely candidate.
Decursin decreases PSA expression and AR protein
abundance[14]
Exposure of LNCaP cells to purified decursin for 48 h in
complete medium decreased cellular and secreted PSA with
an IC50 of ~0.4 µg/mL (1.3 µmol/L) (Figure
2A). Exposure for 24 h to decursin (1.6, 3.3, and 6.6 µg/mL, corresponding to 5,
10 and 20 µmol/L) and AGN extract (5, 10, and 20 µg/mL)
decreased, in a concentration-dependent manner, PSA mRNA
and protein abundance (Figure 2B), recapitulating the
effects of KMKKT. Like KMKKT, decursin or AGN extract
did not affect the AR mRNA level detected by RT-PCR (Figure
2B), but did decrease the AR protein abundance detected by
immunoblot (IB) (Figure 2B).
Growth suppression through G1 arrest[14]
Exponentially growing LNCaP cells were treated in
complete medium containing 10% whole serum for 24 or 48 h before
flow cytometry analyses. AGN extract and decursin induced
potent G1 arrest in a concentration-dependent manner, as did
KMKKT (Table 2). The sub-G1 apoptotic fraction estimation
showed no increase in cell death at the concentrations tested.
Decursin inhibits AR nuclear translocation and
transactivation[14,18]
After androgen binding, AR undergo conformational
change and dimerize and translocate from the cytosol (C) to
the nucleus (N) to activate gene transcription. The blocking
action can be detected in just 1-h pre-treatment in a
concentration-dependent manner (Figure 3). These results
indicated that decursin rapidly inhibited AR translocation into
the N and decreased its protein abundance.
Decursin increases proteasomal degradation of
AR[18]
Given that decursin did not decrease the AR mRNA level
(Figure 2B), we estimated AR protein degradation after
blocking new protein synthesis with
cycloheximide. The data showed increased degradation of AR by decursin treatment
within 3 h (Figure 4A).
As AR is known to be degraded by 26S
proteasome[19], we included the proteasomal inhibitor MG-132 in the
absence of androgen and observed a complete block of AR
downregulation by decursin (Figure 4B, lane 4 vs
lane 3). This inhibitor partially reversed the AR degradation induced
by decursin in the presence of androgen (Figure 4B, lane 8
vs lane 7). The abundance changes in cyclin D1, a protein also
well known to be degraded through the 26S proteasomal
pathway[20], verified the specificity of MG-132. Therefore,
these data supported an induction of proteasomal
degradation of AR by decursin as one mechanism of downregulating
AR protein abundance.
Decursin and AGN extract induce NED, recapitulating the effect of
KMKKT[14]
Incubation of sparsely seeded LNCaP cells in phenol
red-free medium supplemented with 5% charcoal striped serum
(PRFM-CSS) induced NED, which could be reversed by the
addition of mibolerone (Figure 5; photographed 9 d after
seeding, panel a vs panel g). In the absence of androgen
stimulation (panels a_f), decursin (e, f), AGN extract (c, d)
and KMKKT extract (b) decreased the basal PSA secretion
4-fold from 12 ng/mL to 3 ng/mL. In the presence of
androgen (panels g_l), decursin (k, l) and AGN extract (i, j)
inhibited the androgen-stimulated reversal of NED and
androgen-stimulated cell proliferation as well as the inhibited PSA
secretion in a concentration-dependent manner, achieving a
complete block on these parameters with 3.3 µg/mL (10
µmol/L) of decursin and 10 µg/mL of AGN extract, respectively. These
data unequivocally support decursin as an anti-androgen
and AR compound in AGN and KMKKT extracts.
Comparison of decursin analogs from AGN reveals structure-activity relationships on
anti-androgen activity and apoptosis[18]
Other major pyranocoumarin compounds isolated from
AGN include decursinol angelate (DA), which is a decursin
structural isomer on the side chain, and decursinol, which
comprises the pyranocoumarin core but lacks the side chain
of the former two[17,21,22] (Figure 1). DA produced nearly
identical patterns of suppression on PSA protein (Figure 6A by
ELISA and 6B by Western blot analysis). Similar to decursin,
DA decreased AR protein expression (Figure 6B) without
affecting its mRNA.
Surprisingly, decursinol exerted biphasic effects with
respect to exposure concentration on the cellular and secreted
PSA protein levels (Figure 6A, 6B). In particular, at lower
micromolar concentrations, decursinol decreased PSA protein in a
dose-dependent manner as did decursin and DA (Figure 6A).
As the decursinol treatment concentration was increased, PSA
expression was not decreased further, instead it exhibited a
gradual and concentration-dependent recovery, and was
restored to the control cell level with 100 µmol/L decursinol (Figure
6A, 6B). Decursinol did not significantly affect AR protein level
(Figure 6B). We have also shown that decursin is a more potent
competitor than decursinol for DHT binding to
AR[18]. Decursinol did not induce caspase-mediated apoptosis whether
decursin and DA did in the same dose range tested (Figure 6B).
Therefore, the side chain of decursin and DA is essential for the
anti-androgen and apoptotic activities.
Distinct actions from those of
Casodex/bicalu-tamide on PSA and AR protein
abundance[14]
We compared decursin in the presence and absence of
androgen stimulation with bicalutamide, which is an
androgen-binding antagonist[23]. LNCaP cells were cultured in
5% CSS medium for 48 h and exposed to DMSO or indicated
concentrations of decursin or bicalutamide for 1 h before the
addition of mibolerone for 24 h. As shown in Figure 7,
decursin decreased PSA protein as well as AR protein
abundance in the absence (lanes 2 and 3 vs 1) and presence of
mibolerone (lanes 7 and 8 vs 6). In contrast to decursin,
bicalutamide increased the basal levels of cellular PSA as
well as AR abundance in the absence of androgen (lanes 4
and 5 vs 1), acting as a partial AR binding "agonist". As
expected by its androgen-binding blocker action,
bicaluta-mide decreased PSA protein expression in the presence of
mibolerone in a concentration-dependent manner (lanes 9
and 10 vs 6). With respect to LNCaP survival, decursin was
more potent than bicalutamide at the same molar
concentration of exposure (40 µmol/L) in inducing apoptosis as
indicated by the cleaved PARP (lane 3 vs 5; lane 8
vs 10). These results supported distinct novel mechanisms by which
decursin inhibited androgen and AR signaling in
comparison with bicalutamide.
Persistent inhibition of PSA expression by decursin after
removal[14]
Another important feature of decursin is the long-lasting
action on androgen and AR signaling. We exposed LNCaP
cells for 3 d in complete medium with decursin and then
carefully removed the conditioned media and washed the
cells twice with serum-free medium. The cells were then fed
fresh complete medium for 1, 2, or 3 d. At each time point, the
cells were lysed for immunoblot analysis of cellular PSA
(Figure 8). Decursin-treated cells maintained a profound
suppression of cellular PSA throughout 72 h, whereas the AR
protein rebounded to the control level within 24 h after the
removal of decursin. These results suggested that decursin
exerted a sustained inhibitory action on androgen and AR
signaling even after AR protein abundance had fully
recovered.
Reported biological and anti-tumor activities
of pyranocoumarin compounds
Decursin was first isolated from Angelica
decursiva (Fr. et Sav.) in Japan in 1966 and later from Korean
AGN[17,24,25]. Geographical origin appears to make a big difference to
decursin content as shown by Woo et
al[26], who failed to detect decursin in 30 samples of the Chinese Dang-Gui
(Angelica sinesis). This was further supported by a more
recent study comparing Dang-Gui from Korea, China and
Japan[27]. Other major compounds isolated from AGN
include DA and decursinol[21,22,28] (Figure 1). Additional minor
decursin analogs have recently been reported, including
4'-hydroxytigloyldecursinol, 4'-hydroxydecursin,
(2'S,3'S)-epoxyangeloyldecursinol, and
(2'R,3'R)-epoxyangeloyl-decursinol[29].
A US patent (United States Patent 6,525,089 Chong
et al) was granted in February 2003 to the BiNex company in South
Korea as a pharmaceutical with efficacy in ameliorating
diabetic hypertension, prevention of renal failure, prevention
of diabetic complication, prevention of Cisplatin
nephrotoxicity and as a leukemia cell differentiation agent. Decursinol
has been studied for its pain suppressing activity in rodent
models and for protection against memory
loss[30_32]. Other reported activities of decursin and DA include an
antibacterial effect[33] and platelet anti-aggregation
effect[34]. Some other cellular and molecular actions of decursin include
inhibition of lipid droplet accumulation in
macrophages[35], blocking of nuclear factor-kappaB activation in
macrophages[36], activation of PKC and megakaryocytic differentiation of K562
human erythroleukemia cells[16], and anti-leukemic
actions[37].
In terms of the anti-cancer activities, cytotoxic activity of
decursin and DA has been described in leukemia cell lines
in vitro[15,16,21,37]. A recent report has shown that decursin
inhibits the cell cycle and induces apoptosis in LNCaP cells
as well as in androgen-independent DU145 and PC-3 PCa
cells[38], although the concentrations required for these
latter cellular effects were much higher than the
concentrations required for the anti-androgen
effect[14]. Decursinol was found to be much less active than decursin for cell cycle
G1 arrest and apoptosis activity in the DU145 cells. We have
discovered partial agonist activity of decursinol in a LNCaP
model at high concentrations[18] (Figure 6).
The only published animal study evaluating in vivo
anti-cancer activity was reported in
2003[39]. In this study, decursin and DA were found to be active against Sarcoma-180 growth
in mice inoculated subcutaneously at a daily intraperitoneal
injection dose of 50 or 100 mg/kg body weight. The
treatments also prolonged the survival of the sarcoma-bearing
mice. It was communicated at the 2007 American
Association for Cancer Research (AACR) annual meeting in Los
Angeles that orally administered decursin significantly
decreased estrogen-independent breast cancer MDA-MB231
xenograft growth in nude mice[40] These data support the
oral bioavailability of decursin for in
vivo anti-cancer activity. None of these pyranocoumarin compounds has been
evaluated for chemoprevention in primary carcinogenesis models
in any organ site.
Summary and future work
Our data support decursin and DA as members of a novel
class of compounds with potent and long-lasting inhibitory
activities against AR signaling in both ligand-dependent and
ligand-independent ways[14,18], in addition to their other
cellular and molecular actions as summarized above. Decursin
and DA do not possess the weak agonist activity of
bicaluta-mide in the LNCaP model system and are more potent than
this pure anti-androgen at inhibiting cell growth and survival.
The side chain is crucial for the potent and persistent
anti-AR activities, and for the cell cycle arrest and apoptosis
effects[18]. Aside from the rapid block of AR nuclear
translocation, we have identified the following additional
mechanisms to account for the specific anti-AR actions:
inhibition of binding of DHT to AR and increased proteasomal
degradation of AR protein without affecting mRNA level.
However, the pharmacokinetics and metabolism of decursin,
DA and other pyranocoumarins should be investigated to
establish their in vivo stability profiles and metabolites.
Studies in appropriate preclinical animal models are needed to
establish whether decursin and DA express
anti-androgen/AR activity in vivo and whether the anti-cancer activities
result from decursin itself or its metabolites.
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