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Curcumin: a phytochemical modulator of estrogens and androgens in tumors

of the reproductive system

Article in Pharmacological Research · March 2020

DOI: 10.1016/j.phrs.2020.104765

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 Pharmacological Research 156 (2020) 104765

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Invited Review

Curcumin: a phytochemical modulator of estrogens and androgens in tumors T

of the reproductive system
Mohammad Mohajeria, Vanessa Bianconib, Marco Fidel Ávila-Rodriguezc, George E. Barretod,e,
Tannaz Jamialahmadif,g, Matteo Pirrob, Amirhossein Sahebkarh,i,j,*
a
Department of Medical Biotechnology & Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran
b
Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
c
Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia
d
Department of Biological Sciences, University of Limerick, Limerick, Ireland
e
Health Research Institute, University of Limerick, Limerick, Ireland
f
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
g
Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
h
Halal Research Center of IRI, FDA, Tehran, Iran
i
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
j
School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

ARTICLE INFO ABSTRACT

Keywords: Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with
curcumin biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential anti-
hormonal activity tumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-
androgen estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against
estrogen
tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition
cancer
of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk
between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive
and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

1. Introduction type 2 diabetes, obesity, chronic inflammation, psychiatric and re-

Curcumin (Cur; diferuloylmethane) is a natural polyphenol present
in the turmeric (Curcuma longa) rhizomes [1–3]. Due to its broad
spectrum of biological properties [4–13], Cur has been widely re-
cognized to exert potential therapeutic effects against a wide range of
pathologies, including osteoarthritis, cardiac ischemia/reperfusion,
nonalcoholic fatty liver disease, metabolic syndrome, dyslipidaemia,
spiratory diseases as well as some symptoms including pain and prur-
itus [14–21]. In addition, there is growing evidence suggesting that Cur
may exert potential gonado-protective effects [22,23], due to its anti-
oxidant [24], anti-inflammatory [25], anti-cancer [26,27], and anti-
apoptotic activities, as well as its ability to modulate estrogen and an-
drogen activities [28–32].
Various in vitro and in vivo studies suggest that estrogens can

Abbreviations: AKR1C-2, aldoaldo-keto reductase family 1 member C2; Akt, protein kinase B; AP-1, activator protein-1; AR, androgen receptor; ASC-J9, di-
methylcurcumin; BC, breast cancer; b-FGF, basic fibroblast growth factor; CBP, cAMP response element-binding protein (CREB)-binding protein; CDK4, cyclin-
dependent kinase 4; CPM, Cur-loaded POCA4C6 micelles; CRPC, castrate-resistant PC; Cur, curcumin; CYP11A1, cytochrome P450, family 11, subfamily A, poly-
peptide 1; DCIS, ductal carcinoma in situ; DHT, dihydrotestosterone; EGCG, epigallocatechin gallate; EGFR, epidermal growth factor receptor; ER, estrogen receptor;
HC, hydrazinocurcumin; HER2, human epidermal growth factor; HSD3B2, 3 beta- and steroid delta-isomerase 2; ICOS, inducible T cell co-stimulator; IL, interleukin;
JAK, Janus kinase; MCP-1, monocyte chemoattractant protein-1; MHC, major histocompatibility complex; miR, microRNA; MMP-2, matrix metallopeptidase 2; NF-
kB, nuclear factor-KB; PAC, 4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone; PC, prostate cancer; PIAS, protein inhibitor of activated STAT; PLGA,
polylactide-co-glycolide; PSA, prostate-specific antigen; PSMA, prostate specific membrane antigen; RTKs, receptor tyrosine kinases; SAR, structure-activity re-
lationship; STAT3, signal transducer and activator of transcription 3; TIMP-1, tissue inhibitor metalloproteinase 1; TNBC, triple-negative breast cancer; TRAMP,
transgenic adenocarcinoma of the mouse prostate; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor
⁎
Corresponding author at: Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
E-mail addresses: sahebkara@mums.ac.ir, amir_saheb2000@yahoo.com (A. Sahebkar).

https://doi.org/10.1016/j.phrs.2020.104765
Received 2 July 2019; Received in revised form 14 February 2020; Accepted 18 March 2020
Available online 23 March 2020
1043-6618/ © 2020 Elsevier Ltd. All rights reserved.
M. Mohajeri, et al. Pharmacological Research 156 (2020) 104765

carcinogenesis and prostate cancer (PC) progression through the up-

regulation of AR and its target genes [41].
There is evidence showing that Cur and a number of Cur analogs
(Fig. 1) may exert chemopreventive and antitumor effects against
cancers of the reproductive system both in females and males, due to
their ability to modulate estrogen- and/or androgen-related pathways
[42–57]. In this review, we summarize the hormonal effects of Cur and
how they can interfere with estrogen- and androgen-dependent sig-
naling cascades in the most prevalent cancers affecting the reproductive
organs, that is BC, PC and endometrial cancer.

2. The chemopreventive and antitumor potential of curcumin

against tumors of the reproductive organs

Fig. 1. Chemical structure of curcumin and related compounds.
increase the risk of endometrial and breast cancer (BC) by different
molecular mechanisms, including activation of cell growth, reduced
apoptosis, and DNA damage [33–40]. Also, androgens, beyond playing
a pivotal role in the normal prostate growth and functions through
various transcriptional cascades stimulated by binding of androgens to
the androgen receptor (AR), may also contribute to prostate
There is growing body of evidence showing that anticancer effects
of Cur on the reproductive organs are related to the modulation of
androgen and/or estrogen-sensitive molecular targets involved in tu-
morigenesis, cell proliferation and apoptosis. This section reviews
available literature concerning the role of estrogens and androgens in
Cur-mediated anticancer activities against PC, BC and endometrial
cancer.

Fig. 2. Protective effects of curcumin on estrogenic tissues. Curcumin exerts protective effects on both estrogen receptor positive and negative tissues. Evidence
demonstrates the promissory actions of curcumin over endometrial carcinoma and breast cancer cell line models. The mechanism of action of curcumin in en-
dometrial carcinoma involves the diminished expression of growth factors receptors including FGF, HER, EGF, VEGF and PDGF causing reduced proliferation of
cancer cells. Additionally, curcumin exerts anti-proliferative and pro-apoptotic functions via Bax induction (Bax/Bcl-2 ratio > 1). Curcumin also induces Cyt-c
release, modulates P53 and promotes cell cycle arrest by regulation of ß-catenin/Wnt – Cyclin D1 signal pathways. In breast cancer models, curcumin diminishes ERα
expression and induces transcriptional modulation of ER expression via miR synthesis, i.e. miR-15a, miR-16, miR-344 and miR-22. The effects of curcumin also
extends to reduce the invasion and migration via the regulation of mediators such as laminin, MMP-2 and TIMP.

2
M. Mohajeri, et al. Pharmacological Research 156 (2020) 104765

Fig. 3. Effects of curcumin on androgenic tissues. Prostate tissue is a target of androgenic and estrogenic effectors via estrogen receptor beta (ERß), and androgen
receptor (AR). The induction of the prostatic tissue causes hypertrophy, enlargement and urethra obstruction. Chronic prostate (androgenic) stimulation may induce
prostate cancer (PC). Curcumin effects on PC cell models include reduction of cell proliferation, cell migration and androgen receptor expression. The molecular
mechanism involved the inhibition of AP-2γ and c-Jun. Curcumin also inhibits the activity of ß-catenin and NF-kB via Tcf-4, CBP and p300 proteins causing
diminished cell growth and migration. Interestingly, curcumin may also induce pro-apoptotic processes by promoting Cyt-c release and increasing Bax activity. It was
observed that curcumin diminishes PSA levels in cell models and clinical studies.

2.1. The chemopreventive and antitumor potential of curcumin against
prostate cancer
Androgens are crucial for the control of prostate growth as well as
its functions [44,58,59]. However, androgen signaling pathways are
also implicated in PC formation and progression. Indeed, there is
growing body of evidence suggesting that PC progression tends to be
accompanied by an altered expression of AR coregulators (e.g., β-ca-
tenin) [60–67]. In addition, in some cases PCs become androgen-in-
dependent by adjusting to a condition of low or no androgen supply
through either a hyperactive AR or AR gene amplification [68–70].
Noteworthy, intra-prostatic metabolism of androgens to estrogens
through aromatase is important for the growth and function of prostate
gland as well [71–76]. Indeed, estrogen signaling mediated through
estrogen receptor (ER)β negatively modulate prostate cell growth and
migration ability [71,77–85].
Among phytochemicals Cur has been widely studied as a chemo-
preventive and antitumor agent against PC [86]. Available experi-
mental studies suggest that Cur can modulate several androgen and/or
estrogen-dependent cell signaling pathways involved in the survival
and proliferation of PC cells [87–94]. To this regard, some in vitro
studies have demonstrated that Cur can down-regulate the expression
of both androgens and AR and inhibit the AR binding activity to the
androgen-responsive element. In a study by Ide et al. the effects of Cur
(0, 10, 25, and 50 μmol/L) on the suppression of androgen synthesis
were investigated in human PC cell lines (i.e., LNCaP and 22Rv1) [95].
It was found that Cur prevented cell growth and caused apoptosis of PC
cells in a dose-dependent manne by reducing the expression of ster-
oidogenic acute regulatory proteins [i.e., cytochrome P450, family 11,
subfamily A, polypeptide 1 (CYP11A1) and 3 beta- and steroid delta-
isomerase 2 (HSD3B2)] and leading to the decline of testosterone
synthesis. Cur treatment also caused a significant increase in the ex-
pression of aldo-keto reductase family 1 member C2 (AKR1C2), which
was paralleled by a significant reduction of dihydrotestosterone (DHT).
In another study, the treatment of LNCaP cells with Cur (10 to 100 μM)
was associated with a significant dose-dependent suppression of AR
expression through the inhibition of the WnT/β-catenin pathway [96].
Also, in LNCaP and PC-3 cells Cur treatment (0-50 μM) down-regulated
the expression of AR and AR-related cofactors, including activator
protein-1 (AP-1), nuclear factor-KB (NF-kB), and cAMP response ele-
ment-binding protein (CREB)-binding protein (CBP) [46]. In the same
study, Cur also inhibited the transforming activities of both cell lines as
evidenced by the declined colony-forming capacity in soft agar [46]. In
addition, in LNCaP PC cell lines, treatment with Cur (0, 5, 10, 20, 40,
and 80 μM) inhibited the androgen-mediated stimulation of prostate-
specific antigen (PSA) gene expression through the down-regulation of
AR expression and activity [97]. In androgen-dependent LNCaP and
androgen-independent PC-3 cell lines, treatment with Cur (0, 10, 25,

3
M. Mohajeri, et al.
50, 75 and 100 μmol/L) [98] promoted the G2/M cell cycle arrest and
increased the ratios of apoptosis in a dose-dependent manner through
the down-regulation of AR expression. In a study by Banerjee et al. Cur
(0, 5, 10, 15, 20, 25, and 50 μM) was added to reinforce the anti-tumor
properties of docetaxel against androgen-independent PC cells (i.e.
DU145 and PC3) [89]. It was observed that the combined treatment had
a synergistic effect on the prevention of the proliferation and the in-
duction of apoptosis of PC cell lines as compared to Cur or docetaxel
alone [89]. Noteworthy, the combined treatment reduced significantly
the expression of some receptor tyrosine kinases (RTKs), including the
human epidermal growth factor (HER2) and the epidermal growth
factor receptor (EGFR), which are known to stimulate the AR signaling
by a ligand-independent mechanism in the androgen-independent stage
of advanced PC [89,99–101]. In androgen-sensitive LNCaP PC cell line
and its bcl-2 over-expressing relative (LNCaP-bcl-2) it was found that
Cur (5 ± 50 μM) induced apoptosis by down-regulating the expression
of apoptosis suppressor proteins (i.e. bcl-2 or bcl-XL) as well as AR
protein [102]. Furthermore, in an in vitro study Cur was shown to in-
hibit proliferation and migration of androgen-independent PC cell lines
(i.e., DU145 and PC3) through estrogen-like effects, which were re-
versed following the administration of an anti-estrogen (i.e., ICI 182).
This suggested that Cur could potentially prevent the progression of
androgen-independent PC also by modulating ER action [44].
The existence of Cur-mediated anti-androgen effects against PC has
been observed also in some in vivo studies. In prostate tissues from the
transgenic adenocarcinoma of the mouse prostate (TRAMP) model a
four-week oral ingestion of Cur 200 mg/kg/d was associated with a
significant decrease of testosterone and DHT levels, further suggesting
that Cur could possess potent anticancer features owing to the inhibi-
tion of androgen synthesis [95]. In an LNCaP xenograft model, Cur
500 mg/kg was shown to slow tumor growth by 27% during the early
period by inhibiting AR activity [103,104]. In nude mice bearing
LNCaP PC xenografts, a six-week synthetic diet containing 2% Cur re-
duced tumor growth, by reducing the rate of PC cell growth and pro-
moting PC cell apoptosis. In addition, it was associated with a sig-
nificant reduction of microvessel density within excised tumors.
Finally, some clinical studies have shown that Cur may have a ra-
tional as an anti-androgen therapy against PC. In a phase II study en-
rolling 30 patients with metastatic castrate-resistant PC (CRPC) without
any previous chemotherapy intervention, Cur (6,000 mg orally, once
daily) in combination with docetaxel (75 mg/m [2] IV infusion, once
each three weeks for six cycles) induced an objective PSA response
(decrease in the serum PSA of at least 50%) in 17 patients (59%) [105].
However, the combined therapy with docetaxel and Cur in metastatic
CRPC [105] did not show any notable improvement in the overall
survival. In a randomized clinical trial enrolling men who were found
not to have PC in prostate biopsies, the combined effects of Cur (0, 2,
20, and 50 μg/mL) and soy isoflavone (0, 0.1, 1, and 10 μg/mL) on
serum PSA levels were evaluated. The results showed that the PSA le-
vels were significantly reduced by the combined treatment among men
with pre-treatment serum PSA levels ≥ 10 μg/mL [106]. Nonetheless,
despite this preliminary evidence on anti-androgenic effects of Cur in
the clinical setting, Cur effectiveness as anti-cancer therapy against PC
has yet to be fully examined.
2.2. The chemopreventive and antitumor potential of curcumin analogs
against prostate cancer
Some Cur analogs have been shown to act as chemopreventive and
antitumor agents against PC by exerting anti-androgen effects.
Particularly, different experimental studies have demonstrated that the
anticancer effects of some Cur analogs are mediated by the modulation
of AR signaling
A novel Cur analog, dimethylcurcumin (ASC-J9), was identified
through structure-activity relationship (SAR) investigations [47]. In a
study aimed to elucidate if ASC-J9 acted like a conventional androgen
4
Pharmacological Research 156 (2020) 104765
antagonist, that is, exerted its function via competing with androgen
binding to AR, it was found that [47] partial structures of DHT and ASC-
J9 (A-ring of DHT and one phenyl ring of ASC-J9 as well as the hydroxy
groups) were aligned. It was also shown that ASC-J9 and DHT possessed
the same conformations. The binding site of ASC-J9 on AR has not yet
been recognized and whether it forms a bond to the androgen binding
site or how it interacts with AR is still unclear. Nonetheless, in several
experimental studies ASC-J9 has been observed to exert potent anti-PC
effects by targeting either directly or indirectly the AR signaling
pathway [107]. Indeed, ASC-J9 was reported to inhibit CRPC cell
growth and metastasis by promoting the proteasome-mediated de-
gradation of both wild-type AR and mutated AR (i.e., AR-F876 L)
[108–110]. It prevented tumor growth in mice with CWR-22Rv1 xe-
nografts by degrading both full-length and splice variants of AR
[111,112]. It degraded ARs with the F876 L mutation in C4-2 and DU-
145 cells and inhibited PC stem/progenitor cell invasion in mice with
CWR-22Rv1 CD133 + S/P xenografts [110,113]. In LNCaP PC cells, it
was shown to selectively suppress AR expression by promoting the
dissociation between AR and its coregulator ARA70 and leading to the
suppression of AR transactivation [114]. Overall, these findings suggest
that the anti-PC activity of ASC-J9 may be associated with the inhibi-
tion of AR activity. However, it should be highlighted that ASC-J9 was
shown to inhibit cell growth of androgen-dependent LNCaP cells, even
at a concentration of 1 μM, but not that of androgen-independent PC-3
or DU-145 cells at a concentration up to 5 μM [115]. This suggests that
at higher doses ASC-J9 could prevent the proliferation of some AR-
negative PC cells through another functional mechanism than AR de-
gradation.
Recently, numerous additional Cur analogs have been designed as
potential anti-PC drug candidates promoting anti-androgenic effects
[45,47,115]. The structural variations in the novel analogs consist of
substitutions around the biphenyl moiety, heteroaryl replacements of
one or both phenyl rings, alterations in the side chain(s) at the C4
methylene of the linker as well as modulation of the diketone or enol-
ketone moiety and different lengths of the linker. SAR research showed
that a suitable C4-side chain with the right size and physicochemical
characteristics strongly determined their anti-AR activity. Compound 3
with a propionic acid ethyl ester and compound 4 with an acrylic acid
ethyl ester at the C4 methylene group exhibited a great potential not
only to inhibit LNCap PC cell proliferation, but also to interfere with the
transactivation of AR [45,115]. Interestingly compound 4 demon-
strated more potent anti-androgenic activity than compound 3. Com-
pounds 6–9, which are characterized by slight modifications in the C4-
side chains as compared with compound 4, did not demonstrate any
specific anti-androgenic activity; nonetheless, they did reveal con-
siderable cytotoxicity against both LNCap and PC-3 cells, suggesting
that additional mechanisms beyond AR inhibition may explain their
antitumor activity. Compound 10, an analogue of compound 4 which
has free phenolic 4’-OH instead of 4’-OMe groups, failed to impede AR
activity in PC cells [116]. Thus, blockade of the phenolic 4’-OH groups
is likely to promote an anti-androgenic activity. Substituting the two
phenyls with other aryl rings or lengthening/shortening the length of
the linker connecting the two phenyls in Cur analogs was not found to
elevate their anti-androgenic activity, although different Cur analogs
with a shortened linker between two phenyls presented potent antic-
ancer effects [117]. Compound 11 including a 1,4-pentadiene-3-one
moiety was shown to have a potent inhibitory action on LNCaP and PC-
3 cell growth, with an IC50 value of 0.5 ± 0.1 μM and 2.1 ± 1.1 μM,
respectively [118]. However, further investigations are warranted to
understand if this anti-androgenic activity may result from an increased
AR degradation.
Alterations in the enol-ketone moiety in the Cur structure led to
poor anti-androgenic activity, though the majority of these analogs
displayed anticancer or cancer prevention features. Compound 12,
where a 1H-pyrazole ring system substituted the enol-ketone moiety,
unraveled more inhibitory potential against LNCaP cells (IC50:
M. Mohajeri, et al.
3.4 ± 0.9 μM) than PC-3 cells (IC50: 5.6 ± 2.0 μM) [118], suggesting
that AR-mediated pathways may be responsible for these effects.
Whether this selective suppression in AR-positive tumor cells may be
actually related to the anti-AR activity needs further research [107].
The effect of additional Cur analogs, including A10 ((2E,6E)-2,6-bis
(3,4,5-trimethoxybenzylidene) cyclohexanone), B10 ((2E,5E)-2,5-bis
(3,4,5-trimethoxybenzylidene) cyclopentanone) and C10 ((1E,4E)-1,5-
bis(3,4,5-trimethoxyphenyl) penta-1,4-dien-3-one) without a het-
eroatom linker, as well as E10 ((3E,5E)-3,5-bis (3,4,5-trimethox-
ybenzyli-dene) tetrahydropyran-4-one) and F10 ((3E,5E)-3,5-bis (3,4,5-
trimethoxybenzylidene) tetrahydrothiopyran-4-one) with a heteroatom
linker were examined on human PC CWR-22Rv1 and LNCaP cell lines.
Compounds F10 and E10 showed stronger inhibitory effects on the
viability of cultured CWR22Rv1 and LNCaP cell lines as compared with
Cur and other Cur analogs. In addition, they tended to be more potent
inhibitors of AR activity than Cur, A10 and B10 [57].
The production of phase II metabolites (e.g., glucuronidation and
sulfation) [119] as well as the poor bioavailability [120,121] make
unpredictable the pharmacokinetic of Cur in vivo. Piperine conjugation
has been used to prevent Cur hepatic and intestinal glucuronidation and
enhance its bioavailability [122]. Noteworthy, glucuronidation of xe-
nobiotics is known to be possibly implicated in their conversions into
carcinogens and to be involved in tumorigenesis [123]. Therefore, it is
conceivable that piperine-conjugated Cur antitumor effect may be
amplified. In addition, various nanoformulations based on liposomes,
cyclodextrins, polymers, and other special systems of delivery have
been used to improve the bioavailability of Cur [124]. Cur-based na-
noparticle formulations can overcome the problems of poor oral ab-
sorption, probably through intravenous administration and therefore by
effectively modulating the exposure in plasma and promoting deposi-
tion into tumor tissue. In this regard, Yallapu et al. studied an anti-
prostate specific membrane antigen (PSMA)-conjugated Cur-loaded
poly(lactide-co-glycolide) (PLGA) nanoparticle with target selectivity
against PC cells manifesting PSMA in both in vitro and in vivo settings
[125]. Lipid-polymer hybrid nanoparticles containing both docetaxel
and Cur inhibited tumor growth in mice bearing PC-3 PC xenografts,
implying the synergy of these two compounds [126]. A summary of
molecular structure of curcumin and related analogs/compounds is
displayed in Fig. 1.
2.3. The chemopreventive and antitumor potential of curcumin against
breast cancer
BC is the second main contributor of cancer death among women in
the USA [127]. Although limited information is available on the asso-
ciation of circulating estrogen levels in premenopausal women with the
risk of BC, an almost 2-fold higher risk of BC has been observed among
postmenopausal women in the top 20–25% (as opposed to bottom
20–25%) of circulating estrogen levels [128]. Approximately 70% of
BCs are categorized as ER-positive and can be treated using anti-es-
trogens [129,130]. Noteworthy, estrogens have a crucial pathogenic
role also in the early intraductal neoplastic proliferation of epithelial
cells [i.e., ductal carcinoma in situ (DCIS)] preceding ER-positive in-
vasive BC [127,131,132]. Unlike ER-positive BC, triple-negative BC
(TNBC) is a heterogeneous and clinically aggressive disease that lacks
any approved targeted therapeutic approach as it possesses no receptor
for estrogen, progesterone, and human EGFR2 [133]. Since TNBC
progression has been attributed to the up-regulation of β-catenin and
AR, suppressing their expression or activity in BC stem cells can be
useful for the treatment of TNBC [134,135].
Among phytochemicals Cur has been widely studied as a chemo-
preventive and antitumor agent against BC [136–142]. Several in vitro
studies have shown that Cur has inhibitory effects on the proliferation
of human BC cells through the modulation of estrogen-induced ER-
mediated transcription [43]. In ER-positive BC cells, potent anti-pro-
liferative properties of Cur were reported in the presence of
5
Pharmacological Research 156 (2020) 104765
environmental estrogens [43,143]. Cur (0-100 μM) was shown to pre-
vent the proliferation of T-47D BC cells in a dose-dependent manner
through a marked downregulation of ERα, ERβ and leptin [144], the
latter one being an adipocytokine with a crucial role in breast carci-
nogenesis regulated via ER-mediated transcription [144–147]. T-47D
BC cells showed a significantly reduced expression of p53 and ERα
along with a reduced proliferation when treated with 20–80 μM Cur
[140]. The anti-proliferative properties of Cur were dependent on es-
trogens in ER-positive MCF-7 BC cells [43]. However, some in vitro
studies suggested that the presence of estrogens was not necessary for
Cur to exert anti-proliferative effects against BC. Indeed, Hallman et al.
showed that Cur (0, 5, 10, 20, 30, 40, 60, 80, 100 μM) reduced T-47D
BC cell viability regardless the presence of anti-estrogens and ER ago-
nists [140]. Shao et al. reported that Cur (0-50 μM) had suppressive
estrogen-independent effects on the proliferation and invasiveness of
ER-negative MDA-MB-231 BC cell lines [43]. Cur was shown to cause
cell cycle arrest in the G2/S and G2/M phase in a number of BC cell
lines, including those resistant to anti-estrogens [148,149]. Overall,
these findings suggest that additional mechanisms are involved in Cur-
mediated antitumor effects against BC beyond ER signaling pathways.
To this regard, it has recently been shown that Cur can inhibit BC on-
cogenesis partly owing to the modulation of microRNA (miR)-mediated
regulation of protein synthesis [150,151]. The expression of miR-15a,
miR-16 and miR-34a, which downregulate the expression of anti-
apoptotic proteins (e.g., Bcl-2 and Bmi-1), was shown to be increased in
different BC cell lines treated with Cur [152,153]. In MDA-MB-231 and
MDA-MB-435/β4 (β4-integrin transfectants) BC cell lines, Cur treat-
ment was shown to reduce cell motility and invasiveness by down-
regulating the expression of vascular endothelial growth factor (VEGF),
basic fibroblast growth factor (bFGF) and matrix metallopeptidase
(MMP)-2, as well as by upregulating the expression of tissue inhibitor of
metalloproteinase (TIMP-1) [154]. In BT-483 and MDA-MB-23 BC cell
lines, Cur was reported to inhibit BC cell proliferative rate and invasive
ability by down-regulating the expression of cyclin D1, cyclin-depen-
dent kinase 4 (CDK4) and MMP-1 [155]. Cur was also shown to induce
cell cycle arrest at the G2M phase and late S phase in MCF-7 cells, by
suppressing the oncoprotein Aurora-A [156].
Some in vivo studies further support the notion that Cur may exert
antitumor effects in BC by targeting both ER signaling and additional
molecular pathways. Lv et al. reported that Cur treatment led to a
significant reduction of tumor volumes and tumor weight in xenografts
of MDA-MB-231 BC [157]. In athymic nude female mice implanted
with MDA-MB-231 cells, treatment with Cur (200 mg/kg/day, orally)
plus epigallocatechin gallate (EGCG) (25 mg/kg/day, ip) for 10 weeks
led to a 78% reduction in levels of VEGF receptor (VEGFR)-1 within the
tumors, which was paralleled by a 49% reduction in tumor volume with
combined treatment. Noteworthy, Cur treatment alone resulted also in
a marked reduction in tumor protein levels of EGFR and protein kinase
B (Akt) [158].
2.4. The chemopreventive and antitumor potential of curcumin analogs
against breast cancer
Some curcumin analogs have been shown to act as chemopreventive
and antitumor agents against BC by exerting anti-estrogen effects.
Hydrazinocurcumin (HC), a synthetic curcumin analogue, was shown to
decrease the viability and migration ability of BC cell lines (i.e., MDA-
MB-231, MCF-7) by inhibiting signal transducer and activator of tran-
scription 3 (STAT3) phosphorylation and downregulating STAT3
downstream targets, including Bcl-xL, Bcl-2, cyclin D1/D2, VEGF,
MMP-2 and MMP-9 [159]. Encapsulation of ASC-J9 into PLGA nano-
particles resulted in apoptosis of estrogen-dependent BC cells (MCF-7
cells) at lower concentrations than the pure compound [141].
In view of Cur low bioavailability and low efficacy in the form of a
free drug, a new vehicle for in vivo delivery of Cur using the phos-
phorylated calixarene POCA4C6, was developed to assess the
M. Mohajeri, et al.
therapeutic potential of Cur against TNBC. Cur-loaded POCA4C6 mi-
celles (CPM) were developed by means of the thin-film method. The
CPM consists of a unilamellar structure with a mean particle size of
3.86 nm with high Cur encapsulation efficiency and loading as well as a
sustained release of Cur in a pH-dependent manner. This preparation
inhibited the proliferation, invasion, migration, and tumor spheroid
formation of BT-549 and human BC cells. Increased apoptosis and re-
duced levels of nuclear β-catenin and AR were responsible for such
effects. Upon injection into tumor xenografts, CPM remained in the
tumor tissue and efficiently prevented its growth with no obvious sys-
temic toxicity. CPM also reduced the levels of CD44/CD133 BC stem
cells. These effects were hypothesized to be, at least in part, a result of
the disruption of AR-mediated suppressive signaling as well as of
crosstalk between AR signaling and Wnt/β-catenin signaling [160]. In a
comparative study investigating the anticancer effects of Cur and its
analog 4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone
(PAC), PAC was more stable than Cur in phosphate buffered saline and
in circulating blood. Differential sensitivities to PAC were found in ERα
positive and ERα negative BC cells. Indeed, PAC totally inhibited ERα
only in ERα negative cells expressing a very low level of this receptor.
The specific suppression of ERα in receptor-positive cells enhanced the
apoptotic response to PAC, suggesting that ERα may prevent the PAC-
dependent induction of apoptosis via the ERα inhibition. In addition,
PAC down-regulated the proliferation and reduced the epithelial-to-
mesenchymal transition of BC cells both in vivo and in tumor xenografts.
Finally, PAC inhibited the expression/release of two major cytokines
[i.e., interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-
1), and prevented the paracrine procarcinogenic influences of BC cells
on breast stromal fibroblasts [161].
2.5. The chemopreventive and antitumor potential of curcumin/curcumin
analogs against endometrial carcinoma
In endometrial carcinoma cell lines (i.e., HEC-1-A cells), Cur ad-
ministration resulted in DNA degradation, apoptosis-like alterations
and decreased protein expression of the proto-oncogene Ets-1, as well
as the anti-apoptotic molecule Bcl-2, in a time and concentration-de-
pendent manner [162]. Also, in other endometrial carcinoma cell lines
(i.e., Ishikawa and RL95-2 cells) Cur inhibited cell growth and triggered
apoptosis through the inhibition of Janus kinase (JAK)-STAT signaling
via activation of the protein inhibitor of activated STAT (PIAS)-3 and
attenuation of STAT3 phosphorylation [163]. In an in vivo study, Cur
suppressed the mRNA and protein expression of Bcl-2 in endometrial
carcinoma isolated from mice; however, co-administration of letrozole
(an aromatase inhibitor) and Cur promoted tumor cell apoptosis [164].
Recently, the immunomodulatory potential of a Cur analog (i.e., Cur
phytosome) in endometrial carcinoma has been explored in a phase 2
clinical study [165]. After consumption of 2 g/day Cur phytosome or-
ally for 2 weeks, blood samples from seven patients with endometrials
carcinoma showed a significant reduction of the expression levels of
major histocompatibility complex (MHC) on leukocytes and inducible T
cell co-stimulator (ICOS) expression by CD8 + T cells, but no differ-
ences in inflammatory biomarkers, frequencies of immune cells other
than monocytes, and T cell activation. Therefore, whether Cur/Cur
analogues may represent possible immunoregulatory agents against
endometrial carcinoma remains uncertain [166].
3. Conclusions
Growing evidence indicates that Cur and its analogs interact with
androgen and estrogen molecular pathways in different cell types and
conditions (Figs. 2 and 3). Various in vitro studies suggest that Cur and
its analogs can induce BC cell apoptosis and can inhibit the expression
of VEGFR-1, adipocytokines and cytokines by BC cells, by targeting
estrogen signaling pathways. These Cur-mediated effects, which may be
potentially useful for the inhibition of BC growth and progression,
6
Pharmacological Research 156 (2020) 104765
warrant further investigation in in vivo and clinical studies. A number of
in vitro studies also suggest that Cur has multifaceted effects on an-
drogen signaling pathways in PC cells. Indeed, it was shown to promote
the S5αR inhibition, induction of the cell cycle arrest in G2, the mod-
ulation of Wnt/β-catenin signaling, the inhibition of PSA promoter
activity, the suppression of NF-kB activation, the down-regulation of
apoptosis suppressor proteins and AR, the degradation of AR, and the
block of the AR signaling pathway. However, the potential efficacy of
Cur in the treatment of PC needs to be further validated in clinical
trials. Finally, growing experimental evidence showing that Cur may
exert significant antitumor effects against endometrial carcinoma needs
to be corroborated by in vivo and clinical studies.
Declaration of Competing Interest
None
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