Biomedicine & Pharmacotherapy 97 (2018) 91–97

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Curcumin and endometriosis: Review on potential roles and molecular MARK

mechanisms
⁎
Tahereh Arablou, Roya Kolahdouz-Mohammadi
Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Endometriosis, an estrogen-dependent inflammatory disease, is one of the most common chronic gynecological
Curcumin disorders affecting women in reproductive age. It is characterized by the presence of endometrial-like tissue
Endometriosis outside the uterus. The exact pathophysiology of endometriosis is not still well-known, but the immune system
Immune system and inflammation have been considered as pivotal factors in disease progression.
Polyphenol
Turmeric, an important spice all around the world, is obtained from the rhizomes of Curcuma longa, a
Turmeric
member of the Zingiberaceae family. It has been used in the prevention and treatment of many diseases since
ancient times. Curcumin is the principal polyphenol isolated from turmeric. Several evidences have shown the
anti-inflammatory, antioxidant, anti-tumor, anti-angiogenesis, and anti-metastatic activities of curcumin. In this
review, relevant articles on the effect of curcumin on endometriosis and possible molecular mechanisms are
discussed.

1. Introduction endometrial implants into the affected tissues [7].

Endometriosis is one of the most common gynecological disorders
that characterized by the presence of glands and stroma outside the
uterine cavity [1]. It affects 6–10% of women in reproductive age. The
primary symptoms of the disease are infertility and pelvic pain. Other
symptoms include dysmenorrhea, irregular uterine bleeding, dyspar-
eunia, and dysuria [1–3]. Endometriotic lesions are often detected in
the ovaries, fallopian tubes, the ligaments of the uterus, the cervical-
vaginal area, abdominal, wall and umbilicus, urinary tract and also the
rectum [4,5]. The American Society for Reproductive Medicine, has
classified the disease from stage Ι (minimal endometriosis) to stage IV
(severe endometriosis) according to the number, size, morphology,
adhesion, and location of endometrial implants [6]. The clinical pre-
sentation of the disease is classified by the American Fertility Society as
peritoneal endometriosis, endometriotic ovarian cysts and deeply in-
filtrating endometriosis (DIE). DIE, the most aggressive manifestation of
endometriosis, is characterized by penetration more than 5 mm of
The pathogenesis of endometriosis has been much debated and
various hypotheses have been postulated in disease pathogenesis.
According to the Stem cell theory, undifferentiated stem cells like bone
marrow-derived stem cells translocate to ectopic regions and differ-
entiate to endometriotic lesions [8,9]. Metaplasia theory proposed that
residual embryonic cells of the Wolffian or Mullerian ducts transform
into endometrial tissue through hormonal and immunological factors
[8]. Displacement of endometrial tissue outside the uterine cavity
during organogenesis is another theory to describe endometriosis de-
velopment [5]. Among the theories so far expressed, the Sampson’s
implantation theory is more accepted. According to this theory, through
retrograde menstruation, some endometrial cells are transported into
the peritoneal cavity. This phenomenon results in the implantation of
the endometrial cells to the peritoneum and development of en-
dometriotic lesions [10,11]. According to Sampson’s theory, adhesion
and proliferation of endometrial tissue, cellular invasion and neoan-
giogenesis are essential elements in the pathogenesis of endometriosis

Abbreviations: AP-1, activator protein-1; Bax, Bcl-2-associated X protein; Bcl-2, B cell lymphoma-2; CCl4, carbon tetrachloride; COX-2, cyclooxigenase-2; EGF, epidermal growth factor;
ELAM-1, endothelial leukocyte adhesion molecule-1; FGF, fibroblast growth factor; GnRH, gonadotropin releasing hormone; GPx, glutathione peroxidase; HER-2, human epidermal
growth factor receptor-2; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor-1α; HPV, human papilloma viruses; HUVEC, human umbilical vein endothelial cells; ICAM-1,
intracellular adhesion molecule-1; IFN-γ, interferon-γ; IGF-1, insulin-like growth factor-1; Iκ-B, inhibitor of kappa B; IL-6, interleukin-6; IL-8, interleukin-8; MCP-1, monocyte che-
moattractant protein-1; MDA, malonaldehyde; MMP, matrix metalloproteinase; MT1MMP, membrane type 1 matrix metalloproteinase; MVD, microvessel density; NF-κB, nuclear factor-
κB; Nrf2-Keap1, nuclear factor erythroid 2 related factor 2- Kelch ECH associating protein 1; PBMC, peripheral blood mononuclear cells; PDGF, platelet derived growth factor; PDGF-βR,
platelet-derived growth factor-β receptor; ROS, reactive oxygen species; TAC, total antioxidant capacity; TGF-β, transforming growth factor-β; TIMP-2, tissue inhibitor of MMP-2; TNF-α,
tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor
⁎
Corresponding author at: Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Hemmat Highway, Postal code:1449614535 Postal box: 141556171,
Tehran, Iran.
E-mail address: roya_kolahdooz88@yahoo.com (R. Kolahdouz-Mohammadi).

http://dx.doi.org/10.1016/j.biopha.2017.10.119
Received 10 September 2017; Received in revised form 13 October 2017; Accepted 21 October 2017
0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved.
T. Arablou, R. Kolahdouz-Mohammadi
[12]. Thus, cytokines, growth and angiogenic factors, and adhesion
molecules such as TNF-α, IL-6, IL-8, TGF-β, and VEGF have been im-
plicated as inducers of attachment, proliferation, and neovasculariza-
tion [11]. Definitely, the proliferation, invasiveness, and attachment to
the extracellular matrix are greater in ectopic endometrial cells and
these cells produce higher amounts of pro-inflammatory cytokines and
growth factors compared with the eutopic cells [5].
Despite the relatively high prevalence and economic burden asso-
ciated with the disease, its etiology remains elusive [13,14]. To date,
several factors including genetic, epigenetic, anatomic, hormonal, im-
mune, inflammatory, and lifestyle, have considered in disease etiology
[2,9,14]. Some researchers reported that endometriosis is associated
with the quality of life and psychological well-being. Depression and
anxiety are the most common psychological disorders in endometriotic
patients. Sleep disturbance, sadness, dissatisfaction, and loss of working
ability are higher in women with endometriosis compared with healthy
women [7,15].
The only certain method for diagnosis of endometriosis is histolo-
gical analysis after laparoscopy [7,15]. Endometriosis is a chronic dis-
ease in which recurrence may be occurred. Hormone therapy, medi-
cation and surgery are used to alleviate the disease symptoms in
patients. Pain-relievings, non-steroidal anti-inflammatory drugs, GnRH
analogues, aromatase inhibitors, progestins, combined estrogen-pro-
gestin therapy, and selective progesterone receptor modulators are the
most common recommendations [5,16,17]. In some severe conditions
like DIE, surgery is the primary therapeutic [7]. The introduction of
new agents can be effective in improving the condition of patients. Diet
is a potentially modifiable risk factor for endometriosis and recently,
dietary components and phytochemicals are considered as preventive
and therapeutic agents in endometriosis [2,18].
2. Curcumin
2.1. Turmeric
Turmeric that is derived from the rhizome of Curcuma longa L.,
(Zingiberaceae) is used as a spice, flavors, and color, all around the
world. It is native to Asia and it was used in Ayurveda and Tibb-Unani
in the treatment of numerous human diseases such as colic, toothaches,
chest pains, digestive problems, wounds, gynecological problems and
menstrual difficulties since ancient times [19,20].
Turmeric has more than 300 biologically active components such as
polyphenols, sesquiterpenes, diterpenes, triterpenoids, sterols, and al-
kaloids [21]. Curcuminoids, the phenolic compounds derived from
turmeric, are responsible for its yellow color. The three main curcu-
minoids are curcumin, desmethoxycurcumin, and bis-desmethox-
ycurcumin [22].
2.2. Chemistry and health benefits of curcumin
Curcumin (diferuloylmethane), the most active polyphenol in tur-
meric, is a low molecular weight curcuminoid. It was first chemically
characterized in 1910 and comprises 2–8% of most turmeric [23,24].
Curcumin is a strong anti-inflammatory agent. According to litera-
ture, clinical trials have inconsistent results about the effects of cur-
cumin in various disorders [25–28]; but up to now, the anti-oxidant,
anti-inflammatory, hypoglycemic, wound healing, anti-microbial, anti-
tumor, anti-angiogenic, anti-mutagenic, anti-metastatic, and hormonal
regulatory properties of curcumin were reported by numerous in-vitro
and animal studies [19,20,29–31]. Curcumin can inhibit chronic in-
flammation induced diseases such as cancer through various in-
trecellular and extracellular molecular pathways. Several studies have
documented the role of curcumin in the prevention and treatment of
various cancers, including gastrointestinal, respiratory, lymphatic, skin
and reproductive system [32].
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Biomedicine & Pharmacotherapy 97 (2018) 91–97
2.3. Pharmacokinetic of curcumin
The absorption and metabolization of curcumin affect its biological
activity. Pharmacokinetic studies have confirmed that intestine and
liver are major organs for curcumin metabolism [29]. Dietary curcumin
is partially absorbed in the intestine [33]. A considerable portion of the
ingested curcumin is not absorbed, reaches the cecum and colon and
excretes [34]. The main part of ingested curcumin is conjugated with
glucoronate and sulfate in the intestine and only negligible un-
conjugated curcumin is shown in plasma and other organs. After oral
curcumin administration, serum concentrations peak at 1–2 h and are
undetectable by 12 h. The major biliary metabolites in rats are glu-
curonides of tetrahydrocurcumin and hexahydrocurcumin [29,35,36].
The bioavailability of curcumin is modest because of its poor ab-
sorption, low water solubility, rapid metabolism and systemic elim-
ination. Therefore, numerous strategies are made to enhance its bioa-
vailability include using the curcumin metabolic pathway blockers,
nanoparticles, liposomes, phospholipid complexes, and structural ana-
logues [29,37].
2.4. Safety of curcumin
Curcumin is classified as ‘Generally Recognized As Safe’ by the
United States Food and Drug Administration [38]. The only reported
side effect of curcumin in one study was diarrhea [39].
The safety and tolerability of curcumin at high doses in human were
evaluated by several clinical trials. Anecdotal reports suggest that
dietary intake of turmeric up to 1.5 g per day, equal to about 150 mg
per day of curcumin, is well-tolerated in human [40]. Some other stu-
dies claimed that oral doses of curcumin up to 8 and 12 g per day were
safe and well tolerated in patients with pancreatic cancer and healthy
volunteers, respectively [41–43].
3. Molecular mechanisms of curcumin related to endometriosis
So far, there are limited in-vitro and in-vivo studies investigated the
effects of curcumin on endometriosis and its complications. In this re-
view, some recent studies on the effect of curcumin on endometriosis
and possible molecular mechanisms are discussed.
3.1. Cell proliferation and apoptosis
Based on literatures, the endometrial cells from women with en-
dometriosis are different from women without the disease. In en-
dometriosis, proliferation and the ability of endometrial cells to implant
in ectopic locations and survive, increases. Proliferation markers in-
dicated an increase in stromal and epithelial proliferation of eutopic
endometrium in the proliferative phase in endometriosis patients. Also,
the apoptosis of the eutopic and ectopic endometriotic cells is greatly
lower in women with endometriosis compared with free-endometriosis
women due to either intrinsic or brought about by environmental fac-
tors. A reduced sensitivity of endometriotic cells to apoptosis could
promote the dissemination and implantation of these cells to ectopic
sites. This reduced apoptosis is associated with the increased expression
of anti-apoptotic factors (e.g., Bcl-2) and decreased expression of pro-
apoptotic factors (e.g., Bax) [44–49].
So far, some studies have investigated the effects of curcumin on cell
proliferation and apoptosis in endometriosis. In a study conducted by
Zhang et al. to assess the effect of curcumin on endometriosis, eutopic
endometriotic stromal and epithelial cells and normal endometrial
stromal and epithelial cells were isolated from eight premenopausal
endometriosis patients (aged 24–45 years). The cells were cultured in
medium containing curcumin at concentration of 10, 30 or 50 μM at
various time points ranging from 24, 48, 72, and 96 h. Results showed
that curcumin decreased the growth and number of endometriotic
stromal cells in a dose-dependent manner [50].
T. Arablou, R. Kolahdouz-Mohammadi
The effect of curcumin on apoptosis, and endometriosis progression
in BALB-c mice was evaluated in a study by Jana and colleagues (2012).
In phase 1, pre-treatment with different doses (12, 24, and 48 mg/
kgbw) of curcumin were carried out for three days before the induction
of peritoneal endometriosis. In phase 2, curcumin (48 mg/kgbw) or
celecoxib was administered for 5 days after induction of the disease.
The results showed that curcumin decreased the development of peri-
toneal endometrial glands compared with control mice. Also, curcumin
treatment increased the ratio of pro-apoptotic factor Bax/anti-apoptotic
factor Bcl-2, induced the expression of mitochondrial apoptotic factors
such as cytochrome-c and caspase-9 and upregulated the expression of
tumor suppressor protein P53 compared with control group [51].
In other reports, curcumin diminished the volume and weight of
endometriotic tissues in experimental rat model of endometriosis in
time and dose dependent trend [52,53], however, it had no significant
effect on the viability of human endometriotic stromal cells [54].
The effects of curcumin on cell proliferation and apoptosis has been
assessed in several other studies.
Yu and Shah demonstrated that treatment with curcumin induced
DNA degradation apoptosis-like changes in human endometrial carci-
noma HEC-1-A cells. Moreover; it decreased the protein expression of
the proto-oncogene Ets-1 and the anti-apoptotic molecule Bcl-2 in a
time- and dose-dependent trend [55]. In another report, curcumin in-
hibited the mRNA and protein expression of Bcl-2 in endometrial car-
cinoma in mice and the administration of Letrozole with curcumin
enhanced tumor cell apoptosis [56]. Other studies have shown that
curcumin inhibited cell proliferation and induced apoptosis in ovarian,
endometrial, and colon cancer cells [57], it counteracted the pro-
liferative response to estradiol, and induced apoptosis in HPV positive
and negative cervical cancer cell lines [58].
Besides, curcumin modulated the expression and activity of some
growth factors that play critical roles in the proliferation of ectopic cells
such as EGF, HER-2, FGF, VEGF, PDGF, and IGF-1 [59]. Curcumin re-
leased cytochrome-c, activated caspase-8, and reduced Bcl-2, Bcl-Xl,
survivin, and cyclin D1 expressions in cancer cells and inhibited cellular
proteosomal degradation. It also induced apoptosis by the involvement
of p53 protein [38,60–63].
3.2. Angiogenesis
Angiogenesis and new blood supply are essential for the survival of
endometriosis implants attached to the peritoneum and the develop-
ment of endometriosis The peritoneal fluid of women with en-
dometriosis has more angiogenic activity than women without the
disease. The secretion of angiogenic factors into the peritoneal com-
partment augments the microvascularization in the peritoneum
[1,3,64]. VEGF is the most important angiogenic factor in en-
dometriosis [64]. Evidences confirmed that the concentrations of VEGF
in peritoneal fluid from women with endometriosis is higher than
women without endometriosis and its level correlates with the stage of
the disease [65]. VEGF is expressed and secreted by activated perito-
neal macrophages and neutrophils [66–69]. Angiogenin, PDGF, and
some cytokines and growth factors such as IL-8, TGF-β, HGF, ery-
thropoietin, macrophage migration inhibitory factor, neutrophil-acti-
vating factor, and TNF-α which augment in endometriosis, play im-
portant roles in angiogenesis [1,64].
The anti-agiogenic activity of curcumin has been assessed in limited
rodent models of endometriosis where curcumin could reduce MVD in
ectopic endometrium, and the expression of VEGF in serum and ectopic
endometrium, whereas, it had no significant effect on MVD in eutopic
endometrium in one study [52,53,70].
Other studies have shown that curcumin inhibited VEGF expression
in orthotopically implanted pancreatic tumors [71] and ovarian cancer
[72] in nude mice. It reduced sinusoidal angiogenesis and the expres-
sion of pro-angiogenic factors such as HIF-1α, VEGF, VEGF-R2, and
PDGF-βR in rat liver with fibrosis and inhibited the motility and
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Biomedicine & Pharmacotherapy 97 (2018) 91–97
vascularization of hepatic stellate cells [73]. Moreover, curcumin de-
creased the angiogenic transcriptional activator HIF-1α expression and
activation in human hepatocellular carcinoma cells [38].
Thaloor et al. reported that curcumin inhibited the angiogenic dif-
ferentiation of HUVEC on matrigel and reduced vessel formation and
endothelial cell infiltration in matrigel plug [74].
3.3. Inflammation
Endometriosis is associated with an inflammation in peritoneal
cavity [11]. As many other chronic diseases, inflammation has a key
role in the pathogenesis of endometriosis [30]. The alteration of im-
mune cells in peritoneal cavity and ectopic sites in women with en-
dometriosis is identified. The peritoneal fluid of women with en-
dometriosis has shown an increased number of activated macrophages
and increased concentration of pro-inflammatory cytokines such as
TNF-α, IL-1, IL-6, IL-8, and TGF-β compared with women without the
disease [1,30]. These cytokines are secreted from peritoneal macro-
phages, lymphocytes, ectopic endometrial implants, or mesothelial cells
of the peritoneum and maintain the estrogen supply in endometriotic
lesions and promote local aromatase synthesis, which is thought to play
pivotal role in disease progression [75]. These inflammatory mediators
also promote adhesion, growth, and angiogenesis of ectopic en-
dometrial tissues [30].
To date, the anti-inflammatory effect of curcumin on endometriosis
was investigated in limited studies. Kim and colleagues have reported
that treatment of human ectopic endometriotic stromal cells with cur-
cumin markedly inhibited secretion of IL-6, IL-8, and MCP-1 and the
activation and translocation of NF-κB [54].
Based on data from other studies, treatment with curcumin, has
increased Iκ-B expression, reduced the nuclear translocation of NF-κB,
and attenuated the expression of TNF-α in endometriotic mice [51,76].
The anti-inflammatory effect of curcumin in other diseases has in-
vestigated in several studies.
In the study of Soetikno et al., on rats under nephrectomy, curcumin
treatment significantly reduced the level of MDA, activity of NF-κB, the
protein and mRNA expression of TNF-α, and COX-2 abundance in the
remnant rat kidney [77]. In the study of Fu et al. curcumin reduced the
levels of inflammatory cytokines, including IFN- γ, TNF-α, IL-6 and also
PDGF, and TGF-β in liver cells in rat liver injured by CCl4 [78].
In other studies, curcumin decreased inflammation through down-
regulating the expression of inflammatory markers such as NF-κB in
mouse macrophages, myeloid leukaemia, and non-Hodgkin’s lym-
phoma, IL-1β, IL-6, and IL-8 in mouse macrophages, esophageal epi-
thelial, and head and neck cancer, MCP-1 in adipocytes, and TNF-α in
mouse macrophages, diabetic encephalopathy, and acute pancreatitis in
rats and also, curcumin suppressed TNF-signaling pathways [38,79].
Moreover, it inhibited the activation and signaling of NF-κB by
blocking phosphorylation of I-κB [80] through inactivation of I-κB ki-
nase complex [81] and inhibited the AP-1, which regulate the expres-
sion of pro-inflammatory mediators and protective antioxidant genes.
The suppression of AP-1 may be due to a direct interaction of curcumin
with AP-1 binding to its DNA binding motif and also due to inhibition of
its components c-Jun and c-fos [31].
Overexpression of COX-2 enzyme has been linked to tumor cell
proliferation and suppression of apoptosis [82]. Several studies have
reported that curcumin inhibited the expression of COX-2 in different
animal models and cell cultures [71,83,84].
3.4. Oxidative stress
Another important potential factor involved in the pathophysiology
of endometriosis is oxidative stress [11]. It has been suggested that
some factors such as enhanced activated macrophages, iron accumu-
lation or environmental contaminants disrupt the balance between ROS
and antioxidants, lead to oxidative stress. Elevated ROS is a key factor
T. Arablou, R. Kolahdouz-Mohammadi Biomedicine & Pharmacotherapy 97 (2018) 91–97

Table 1
Studies on the effect of curcumin on endometriosis.

Author,date (Ref) Endometriosis model Curcumin preparation Intervention duration Main results

Jana et al., [70] Peritoneal endometriotic mice
Zhang et al., [50] Human eutopic endometriotic
stromal and epithelial cells
Jana et al., [51] Peritoneal endometriotic mice
Jana et al., [96] Peritoneal endometriotic mice
Yun-fei et al., [52] Endometriotic rats
Kim et al., [54] Human ovarian endometriotic
stromal cells
Zhang et al., [53] Peritoneal endometriotic rats
Swarnakar and Paul, Peritoneal endometriosis mice
[76]
40 mg/kgbw curcumin nano- 14 days
particles & curcumin-Letrozole nano-particles
Curcumin 10, 30, 50 μM 24, 48, 72, 96 h
1- Pretreatment: 12, 24, 48 mg/kg curcumin 1–3 days before induction of
endometriosis
2- Treatment: 48 mg/kg curcumin 2–5 days after induction of
endometriosis
48 mg/kg curcumin 3 days
150 mg/kg curcumin 3 weeks
1, 5, 10, 20, 30, 50 μM curcumin 24 h
50, 100, 150 mg/kg curcumin 4 weeks
1-Pre-treatment 16, 32, 48 mg/kg curcumin 1–3 days before induction of
endometriosis
2- Treatment 48 mg/kg curcumin 2–10 and 20 days after
induction of endometriosis
Serum VEGF ↓
Microvessel density ↓
Serum MMP-2 ↓
Serum MMP-9 ↓
Serum ROS ↓
Lipid peroxidation ↓
Serum TAC ↑
The number of endometriotic
stromal cells↓
Cell growth ↓
Serum E2 level ↓
MMP-3 expression ↓
Iκ-B expression ↑
NF-κB nuclear translocation ↓
Development of peritoneal
endometrial glands ↓
The ratio of Bax/Bcl-2 ↑
Cytochrome-c and Caspase-9
expression ↑
P53 expression ↑
Unchanged Fas/Fas ligand
pathway
Production of active MMP-2 ↓
MMP-2 expression ↓
TIMP-2 expression ↑
MT1MMP expression ↓
Volume and weight of
endometriotic foci ↓
Microvessel density ↓
Unchanged serum E2 level
Unchanged cell viability
ICAM-1 and VCAM-1 mRNA and
protein expression ↓
ICAM-1 and VCAM-1 cell surface
expression ↓
IL-6, IL-8 and MCP-1 secretion ↓
NF-κB activation and nuclear
translocation ↓
Ectopic tissue volume ↓
VEGF protein expression ↓
Microvessels density ↓
MMP-9 activity and expression ↓
TNF-α expression ↓
TIMP-1 expression ↓
Lipid peroxidation ↓
Protein oxidation ↓

VEGF: vascular endothelial growth factor, MMP:matrix metalloproteinases, ROS: reactive oxygen species, TAC: total antioxidant capacity, E2: estradiol, NF-κB: nuclear factor kappa-light-
chain-enhancer of activated B cells, Bcl-2: B cell lymphoma-2, Bax:Bcl-2-associated X protein, TIMP-2: tissue inhibitor of MMP-2, MT1MMP: membrane type 1 matrix metalloproteinase,
ICAM-1: intracellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-1, IL-6: interleukin-6, IL-8: interleukin-8, MCP-1: monocyte chemoattractant protein-1, TNF-α:
tumor necrosis factor-α.

for disease development and the extension of oxidative stress in the
peritoneal environment may be associated with endometriosis and in-
fertility. Some studies have suggested that ROS or free radicals may
increase growth and adhesion of endometrial cells in the peritoneal
cavity, promoting endometriosis and infertility [10,11].
To the best of our knowledge, a few studies have investigated the
anti-oxidant effect of curcumin on endometriosis. The effect of cur-
cumin nanoparticles with and without Letrozole on endometriosis was
assessed in the study of Jana et al. Results revealed a significant re-
duction in serum ROS and lipid peroxidation and an increase in TAC
after administration of Letrozole-curcumin-nanoparticles and also cur-
cumin-nanoparticles in mice with endometriosis compared with en-
dometriotic control mice [70].
In addition, Swarnakar & Paul have found that the lipid peroxida-
tion and protein oxidation were prevented in endometriotic mice by
curcumin treatment [76].
Several researchers have assessed the antioxidant property of cur-
cumin in other diseases. Soetikno et al. have reported that treatment
with curcumin prevented the decrease in GPx activity and attenuated
oxidative stress, and renal fibrosis by modulating the regularoty
pathway Nrf2-Keap1 in rats under nephrectomy [77]. In another study,
curcumin increased the glutathione content and decreased the level of
lipid hydroperoxide in rat liver injured by CCl4 [78].
Several lines of evidence indicate that the antioxidant activity of
curcumin is comparable to vitamins C and E [85]. It has the potential to
scavenge the variety of free radicals, including ROS and nitrogen di-
oxide radicals [86–88]. It also inhibited lipid peroxidation in different
animal models [89,90]. Curcumin diminished the expression of nitric
oxide synthase in mouse macrophage [91], and increased glutathione in
lymphocytes [92], haem oxygenase-1 in epithelial/HUEVC hybridoma

94
T. Arablou, R. Kolahdouz-Mohammadi
Proliferation&
Apoptosis
Cells number
Cells growth
Bax/Bcl-2
Cytochrome-c
Caspase-9
P53
Angiogenesis
Serum VEGF
MVD
Curcumin
Oxidative
Stress
ROS
Serum TAC
Lipid peroxidation
Protein oxidation
[93], and porcine renal epithelial [94], and superoxide dismutase in
lymphocytes [92].
3.5. Invasion and attachment
The unusual expression of adhesion molecules in endometriosis
leads to the attachment of endometrial-like tissues to ectopic sites and
disease development [30,75]. Evidence suggest that ectopic en-
dometriotic cells have the ability to invade the surrounding tissues and
sometimes to metastasize in lymph nodes and abdominal cavity [95].
The peritoneum of women with endometriosis demonstrated an in-
crease in the production of MMPs especially MMP-1, MMP-2, MMP-3,
MMP-9, and MMP-11, and cellular adhesion molecules, including IC-
AM-1, integrins and cadherins; that play essential roles in tissue at-
tachment and invasion of ectopic lesions in endometriosis. MMPs also
play a key role in implants progression and angiogenesis [30,51,96,97].
The effect of curcumin on adhesion molecules and MMPs involved
in cells invasion and attachment has been reported by several re-
searchers. Jana et al. have shown that curcumin nanoparticles, with and
without Letrozole decreased serum MMP-2 and MMP-9 in en-
dometriotic mice compared with endometriotic control mice [70]. In
another study by Jana and colleagues, treatment with curcumin
downregulated the MMP-3 expression in endometriotic mice compared
with control group [51]. They also showed that in endometriosis model
of BALB/c mice, intraperitoneal injection of curcumin at a dose of
48 mg/kg once daily for three days, inhibited the expression and acti-
vation of MMP-2, upregulated the expression of TIMP-2 and down-
regulated the expression of MT1MMP [96].
Kim and colleagues have reported that curcumin suppressed the
Biomedicine & Pharmacotherapy 97 (2018) 91–97
Fig. 1. Potential roles and molecular mechanisms of
curcumin on endometriosis.
VEGF: vascular endothelial growth factor,
MMP:matrix metalloproteinases, ROS: reactive
oxygen species, TAC: total antioxidant capacity, NF-
κB: nuclear factor kappa-light-chain-enhancer of
activated B cells, Bcl-2: B cell lymphoma-2, Bax:Bcl-
2-associated X protein, TIMP: tissue inhibitor of
MMP, MT1MMP: membrane type 1 matrix metallo-
proteinase, ICAM-1: intracellular adhesion molecule-
1, VCAM-1: vascular cell adhesion molecule-1, IL-6:
interleukin-6, IL-8: interleukin-8, MCP-1: monocyte
chemoattractant protein-1, TNF-α: tumor necrosis
Inflammation factor-α, MVD: microvessel density, Iκ-B: inhibitor of
kappa B.
Iț-B
NF-țB
IL-6
IL-8
MCP-1
TNF-Į
Invasion &
Attachment
MMP-2
MMP-9
MMP-3
TIMP-1
TIMP-2
MT1MMP
ICAM-1
VCAM-1
mRNA and total protein expression of ICAM-1 and VCAM-1 in a dose-
dependent manner in human ovarian endometriotic stromal cells [54].
In another study, curcumin inhibited MMP-9 expression and activity
during regression of endometriotic lesions in a time and dose dependent
manner and attenuated the expression of TIMP-1 in endometriotic mice
[76].
Besides, curcumin inhibited endometrial carcinoma cell migration
and invasion in vitro. It decreased the expression of MMP‐2 and MMP‐9
as well as proteinase activity in these cells [98]. Moreover, it inhibited
K1 papillary thyroid cancer cells invasion, cell attachment and
spreading dose-dependently, suppressed the expression and activity of
MMP-9 and inhibited cell migration stimulated by VEGF in a both dose-
and time-dependent manner [99].
MMPs were down-regulated by curcumin in various cell types
[31,100]. Curcumin decreased production and activity of MMP-2 and
MMP-9 in human fibrosarcoma cells [101]. Recently, it has been shown
that curcumin can reduce MMP-9 expression in PBMC [102], human
intestinal epithelial cells [103], orthotopically implanted pancreatic
tumors [71], ovarian tumors in nude mice [72] and can reduce the
MMP-3 production in primary human colonic myofibroblasts [104].
Other studies have suggested that curcumin decreased expression of
adhesion molecules, including ELAM-1, ICAM-1, and VCAM-l in en-
dothelial cells and in orthotopically implanted pancreatic tumors in
mice [71,105], thus it can reduce cell adhesion and attachment
(Table 1, Fig. 1).
4. Conclusion
The results of related in vitro and animal studies have shown that
95
T. Arablou, R. Kolahdouz-Mohammadi
treatment with curcumin reduces inflammation through suppression of
inflammatory cytokines expression. It also can inhibit invasion, at-
tachment, and angiogenesis of endometrial lesions. Moreover, cur-
cumin inhibits cell proliferation and causes cell cycle arrest and apop-
tosis. Thus, it may has potential benefits as a dietary and
pharmacological agent for the prevention and treatment of en-
dometriosis. However, according to the limited studies in this field and
inconsistent results of clinical trials on the effects of curcumin on some
other diseases, further studies, especially clinical trials are suggested to
investigate the effect of curcumin on endometriosis.
Conflicting interests
The authors report no conflicting interests.
Authors' contribution
TA proposed the research idea, performed the article search, iden-
tified eligible studies and drafted the manuscript. RKM assisted in the
design of the manuscript and in the writing process. All authors read
and approved the final version of the manuscript.
Acknowledgment
The paper has been prepared without any financial supports.
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