curcuminasananti inflammatoryagent:implications...
TRANSCRIPT
Received: 13 August 2018 | Accepted: 27 August 2018
DOI: 10.1002/jcp.27442
R EV I EW ART I C L E
Curcumin as an anti‐inflammatory agent: Implicationsto radiotherapy and chemotherapy
Bagher Farhood1 | Keywan Mortezaee2 | Nasser Hashemi Goradel3 |Neda Khanlarkhani4 | Ensieh Salehi4 | Maryam Shabani Nashtaei4,5 | Masoud Najafi6 |Amirhossein Sahebkar7,8
1Departments of Medical Physics and
Radiology, Faculty of Paramedical Sciences,
Kashan University of Medical Sciences,
Kashan, Iran
2Department of Anatomy, School of Medicine,
Kurdistan University of Medical Sciences,
Sanandaj, Iran
3Department of Medical Biotechnology,
School of Advanced Technologies in Medicine,
Tehran University of Medical Sciences,
Tehran, Iran
4Department of Anatomy, School of Medicine,
Tehran University of Medical Sciences,
Tehran, Iran
5Department of Infertility, Shariati Hospital,
Tehran University of Medical Sciences,
Tehran, Iran
6Department of Radiology and Nuclear
Medicine, School of Paramedical Sciences,
Kermanshah University of Medical Sciences,
Kermanshah, Iran
7Neurogenic Inflammation Research Center,
Mashhad University of Medical Sciences,
Mashhad, Iran
8Biotechnology Research Center,
Pharmaceutical Technology Institute, School of
Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
Correspondence
Masoud Najafi, Department of Radiology and
Nuclear Medicine, School of Paramedical
Sciences, Kermanshah University of Medical
Sciences, Kermanshah 6719851351, Iran.
Email: [email protected]
Amirhossein Sahebkar, Biotechnology
Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical
Sciences, Mashhad 9177948564, Iran.
Email: [email protected];
Abstract
Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are
the most common modalities for the treatment of cancer. Experimental studies have
shown that inflammation plays a central role in tumor resistance and the incidence of
several side effects following both chemotherapy and radiotherapy. Inflammation
resulting from radiotherapy and chemotherapy is responsible for adverse events such
as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic
inflammation may also lead to the development of second cancer during years after
treatment. A number of anti‐inflammatory drugs such as nonsteroidal anti‐inflammatory agents have been proposed to alleviate chronic inflammatory reactions
after radiotherapy or chemotherapy. Curcumin is a well‐documented herbal anti‐inflammatory agents. Studies have proposed that curcumin can help management of
inflammation during and after radiotherapy and chemotherapy. Curcumin targets
various inflammatory mediators such as cyclooxygenase‐2, inducible nitric oxide
synthase, and nuclear factor κB (NF‐κB), thereby attenuating the release of
proinflammatory and profibrotic cytokines, and suppressing chronic production of
free radicals, which culminates in the amelioration of tissue toxicity. Through
modulation of NF‐κB and its downstream signaling cascade, curcumin can also reduce
angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its
cytoprotective effects in normal tissues. This protective action along with the
capacity of this phytochemical to sensitize tumor cells to radiotherapy and
chemotherapy makes it a potential candidate for use as an adjuvant in cancer
therapy. There is also evidence from clinical trials suggesting the potential utility of
curcumin for acute inflammatory reactions during radiotherapy such as dermatitis
and mucositis.
K E YWORD S
cancer, chemotherapy, curcumin, inflammation, radiotherapy
J Cell Physiol. 2018;1–13. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1
1 | INTRODUCTION
After cardiovascular diseases, cancer is the second cause of death in
worldwide (Siegel, Miller, & Jemal, 2015). Each year several million
people undergo different modalities for treatment of cancer (Miller
et al., 2016). The widest modalities for cancer therapy are
chemotherapy and radiotherapy. Although, immunotherapy is the
most interesting modality for the eradication of tumor cells, it need
to more studies for development and confirmation of new drugs
(Kang, Demaria, & Formenti, 2016). Yet, radiotherapy and che-
motherapy are the more common compared with immunotherapy for
cancer therapy, especially in countries with low income (Bazargani,
de Boer, Schellens, Leufkens, & Mantel‐Teeuwisse, 2014). In spite of
beneficial role of these modalities for cancer treatment, there are
some concerns related to early and late side effects of them that may
affect quality of life of patients that undergo chemotherapy and
radiotherapy (Najafi, Motevaseli, et al., 2018). Emerging evidence
show that inflammation caused by radiotherapy and chemotherapy
has a central role for the development of various side effects that
may appear during or after treatment (Yahyapour, Motevaseli, et al.,
2018). Also, inflammation can significantly affect therapeutic out-
come of radiotherapy and chemotherapy (Barker, Paget, Khan, &
Harrington, 2015). Acute inflammation may lead to some severe
reactions in normal tissues that have high sensitivity or are under
expose to massive doses of ionizing radiation. Inflammation in some
of organs, such as tongue and gastrointestinal system, lead to
mucositis that potently affect the quality of life of patients. However,
inflammatory responses in some organs like lung may lead to acute
pneumonitis or fibrosis that threat life of patients (Cheki et al., 2018;
Yahyapour, Amini, Rezapoor, et al., 2018). Dermatitis is a common
side effect of radiotherapy that is resulting from damage to basal
layers of skin (Hymes, Strom, & Fife, 2006). An addition to severe
side effects, chronic inflammation has a potent link to carcinogenesis
(Farhood et al., 2018).
There is a growing interest in traditional medicine‐based therapy
for several diseases including inflammatory diseases. This is because of
low toxicity and lower side effects compared with chemical anti‐inflammatory drugs. The most of anti‐inflammation drugs such as
nonsteroidal anti‐inflammatory drugs (NSAIDs) may lead to increased
risk of cardiovascular diseases and also problems in calcium absorption
(Stock, Groome, Siemens, Rohland, & Song, 2008). Curcumin is the
Asian yellow spice, which is derived from the roots of the Curcuma
longa. Several studies have shown that curcumin can be proposed as a
promising anti‐inflammatory agent (Basnet & Skalko‐Basnet, 2011;Sahebkar, Cicero, Simental‐Mendia, Aggarwal, & Gupta, 2016). By
contrast to NSAIDs, curcumin not only has no a serious side effect, it
can reduce risk of cardiovascular disorders (Qadir, Naqvi, &
Muhammad, 2016). Curcumin has shown promising properties that
are interesting for patients with cancer. In experimental studies, it has
shown is able to ameliorate toxic effects of chemotherapy and
radiotherapy. Antioxidant effect of curcumin help to scavenging of free
radicals which are produced by ionizing radiation and some
chemotherapeutic agents such as cyclophosphamide (Hatcher, Planalp,
Cho, Torti, & Torti, 2008). This is associated with reduced chromosome
aberrations and genomic instability, which is a hallmark of second
primary cancers (Hatcher et al., 2008). Also, curcumin through
modulation several signaling pathways reduces appearance of several
early and late side effects of ionizing radiation and chemotherapy
agents (Bar‐Sela, Epelbaum, & Schaffer, 2010). In this review, we
aimed to explain molecular anti‐inflammation properties of curcumin
in cancer treatment with radiotherapy and chemotherapy.
2 | INFLAMMATION IN CANCER
In addition to tumor cells, a tumor is consisting of a mixture of
different types of cells such as immune cells and some other
nonmalignant cells like fibroblasts, endothelial, and epithelial cells.
The response of tumor cells to radiotherapy, chemotherapy, or
immunotherapy is highly depending to these cells. These cells
together to tumor cells make an environment named tumor
microenvironment (Junttila & de Sauvage, 2013). Inflammatory cells
including macrophages, lymphocytes, and dendritic cells play a key
role in response of tumor, as well as progression of it following
therapy (Jain, 2013). Although, these cells can eradicate tumor cells,
emerging evidence show that inflammatory responses by these cells
play a key role in tumor growth and angiogenesis (Kershaw, Devaud,
John, Westwood, & Darcy, 2013; Liyanage et al., 2002).
Following tumor exposure to therapeutic agents such as
radiation or chemotherapy, a large number of cells undergo death
through different mechanisms, including apoptosis, mitotic cata-
strophe, necrosis, autophagy, and senescence. Among them,
apoptosis and necrosis have pivotal role in the balance between
inflammation and tolerogenic responses. Apoptotic bodies may
digest by macrophages and do not able to stimulate inflammatory
responses by lymphocytes or dendritic cells. However, necrosis
cause release of several danger molecules that are able to induce
inflammation. Also, a high rate of cell death by apoptosis may
overwhelm this type of death of cells, leading to necroptosis, a
phenomenon that apoptosis followed by necrosis. Similar to
necrosis, necroptosis is able to stimulate inflammatory responses
(Yahyapour, Amini, Rezapour, et al., 2018). Inflammatory mediators
play a key role in the angiogenesis and growth of cancers. Nuclear
factor κB (NF‐κB) is regarded as one of the most important links
between cells death, inflammation, and tumor resistance. It has
been shown that cisplatin stimulate upregulation of NF‐κB via PI3/
Akt‐signaling cascade in human ovary cancer cells (Ohta et al.,
2006). Clinical studies also showed that chemotherapy by cisplatin
cause increased expression of NF‐κB in ovarian cancer patients
(Annunziata et al., 2010).
NF‐κB via upregulation of cyclooxygenase‐2 (COX‐2) stimulates
release of prostaglandins and resistance of tumor cells to apoptosis.
Also, it induces vascular endothelial growth factor (VEGF), which
promotes development of new vascular. Signal transducer and
activator of transcription 3 (STAT‐3) and hypoxia‐inducible factor 1
are other inflammation mediators that are involved in tumor
2 | FARHOOD ET AL.
resistance through stimulation of cell proliferation and resistance to
apoptosis. It seems that upregulation of TLR‐4 is involved in
stimulation of NF‐κB and resistance to chemotherapy (Rajput, Volk‐Draper, & Ran, 2013). Inhibition of NF‐κB has proposed for
increasing efficiency of radiotherapy and chemotherapy drugs such
as paclitaxel (Mabuchi et al., 2004; Yahyapour et al., 2017).
3 | INFLAMMATION OF NORMAL TISSUESFOLLOWING RADIOTHERAPY
Inflammation is responsible for several side effects of exposure to
ionizing radiation in normal tissues. Studies have shown that chronic
inflammation that is a common side effect of radiotherapy can induce
genomic instability through stimulation of free‐radical production and
inhibition of DNA repair pathways (Najafi, Cheki, et al., 2018). Also,
chronic inflammation can appear as several side effects in different
organs, such as pneumonitis and fibrosis in the lung, dermatitis in the
skin, enteritis in intestine, proctitis in colon, edema in muscles, and so on
(Yahyapour, Shabeeb, et al., 2018). The origin of radiation‐inducedinflammation is related to DNA damage and cell death. Massive damage
to nucleus DNA by ionizing radiation interactions or free radicals may
lead to cells death because of overwhelm of DNA repair mechanisms.
Immunogenic and tolerogenic types of cells death lead to release
various contents of cells including damage‐associated molecular
patterns (DAMPs). DAMPs including uric acid, heat‐shock proteins,
high‐mobility‐group box 1, and so on, can recognized by some receptors
on the surface of macrophages and dendritic cells, which are named toll‐like receptors (TLRs). TLRs facilitate the response of lymphocytes to
danger alarms. This lead to upregulation of inflammatory mediators
such as NF‐κB, intracellular adhesion molecules (ICAM), STATs, and
some other, which lead to secretion of various inflammatory cytokines
(Najafi, Motevaseli, et al., 2018).
Abnormal increased level of inflammatory cytokines leads to
various side effects in different organs. Pneumonitis in the lung is
resulting from a massive release of interleukin‐1 (IL‐1), IL‐6, IL‐8,tumor necrosis factor α (TNF‐α), and interferon γ ( IFN‐γ). Thesecytokines also via regulation of some pro‐oxidant and profibrotic
enzymes stimulate accumulation of collagen leading to fibrosis.
Both pneumonitis and fibrosis are serious side effects that may
lead to death of patients with cancer. This issue has observed for
patients with chest cancer, as well as other cancers with lung
metastasis (Yahyapour, Shabeeb, et al., 2018). Inflammasome is a
complex that is involved in secretion of IL‐1 following exposure of
cells to ionizing radiation. Mitochondria injury by ionizing
radiation stimulate upregulation of inflammasome (Abderrazak
et al., 2015). Experimental studies have revealed that this
pathway is involved in radiation‐induced mucositis in the tongue
and intestine (Fernández‐Gil et al., 2017; Ortiz et al., 2015). Also,
it seems that dermatitis following skin irradiation has a potent
relation to inflammasome (Favero, Franceschetti, Bonomini,
Rodella, & Rezzani, 2017). Experimental studies show that
pericarditis in heart play a key role in the development of cardiac
disorders in patients with chest cancer. Studies have proposed
that an abnormal increase in the level of some cytokines such as
IL‐1 and TGF‐β play a key role in late effects of ionizing radiation
on cardiac function (Boerma et al., 2016; Eldabaje, Le, Huang, &
Yang, 2015). Increased inflammatory responses and subsequent
chronic production of free radicals following exposure to ionizing
radiation have observed for bone marrow, vascular, brain, joints,
mammary cells, and others (Robbins & Zhao, 2004).
4 | INFLAMMATION OF NORMAL TISSUESFOLLOWING CHEMOTHERAPY
Inflammation plays a key role in the appearance of side effects of
chemotherapy drugs. It is proposed that inflammation caused by
chemotherapy drugs may lead to stimulation of metastasis, cancer
relapse, and even fail of cancer treatment (Demaria et al., 2017;
Vyas, Laput, & Vyas, 2014). Moreover, some evidence show that
inflammation may is involved in some behavioral changes such as
cognitive problems, fatigue, and neuropathy (Vichaya et al., 2015).
It has been shown that NF‐κB and TNF‐α play a key role in
nephrotoxicity following injection of cisplatin to rats (Hagar,
Medany, Salam, Medany, & Nayal, 2015). TNF‐α and its down-
stream signaling such as TNFR1 and p38 have key role for
induction of apoptosis and necrosis in tubular cells following
exposure to chemotherapy agents (Luo et al., 2008; Ramesh &
Reeves, 2003). It seems that it through activation of caspase‐3pathway is involved in cisplatin nephrotoxicity. Suppression of
this mediators showed that attenuate cisplatin‐induced nephro-
toxicity (Arjumand, Seth, & Sultana, 2011). In addition, it is
proposed that cisplatin through stimulation of COX‐2 upregula-
tion is involved in appearance of nephrotoxicity (Domitrović et al.,
2013). Zhou et al. showed that injection of cisplatin to mice lead
to infiltration of inflammatory cells including macrophages and
lymphocytes in kidneys. Moreover, their results showed a
significant increase in the level of inflammatory cytokines
including IL‐1, IL‐6, and TNF‐α. This study showed that inhibition
of apoptosis pathway plays a key role in nephrotoxicity induced
by cisplatin (J. Zhou et al., 2017). Paclitaxel and methotrexate are
other major chemotherapy agents used in clinical oncology.
Experimental studies showed that they are able to induce
oxidative injury and increase of inflammatory cytokines such as
IL‐1, IL‐6, TNF‐α, and IL‐8 (Ibrahim, El‐Sheikh, Khalaf, & Abdelrah-
man, 2014; Pusztai et al., 2004). Lian et al. evaluated irinotecan
(CPT‐11) effect on inflammation pathway in mice intestine. They
showed that DNA damage by CPT‐11 lead to release of exosome
secretion and stimulation of innate immune responses. This lead
to secretion of IL‐1 and IL‐13 through stimulation of inflamma-
some pathway (Lian et al., 2017).
Activation of redox system and chronic oxidative stress
through a chronic inflammatory responses play central role for
chemotherapy‐induced tissues injury. El‐Naga (2014) showed that
injection of cisplatin to rat is associated with increased the
FARHOOD ET AL. | 3
expression of NOX1 and inducible nitric oxide synthase (iNOS) in
kidney, two major reactive oxygen species (ROS) and nitric oxide
(NO) producing enzymes in inflammation conditions. Some other
studies showed increased free‐radical production by mitochondria,
upregulation of heme oxygenase‐1, as well as inhibition of
antioxidant enzymes (Chtourou, Aouey, Aroui, Kebieche, & Fetoui,
2016; Nafees, Rashid, Ali, Hasan, & Sultana, 2015; Ramesh &
Reeves, 2004; Santos et al., 2007). Increased oxidative injury
following administration of chemotherapy drugs such as cisplatin
and cyclophosphamide have confirmed in several studies (Y. Chen,
Jungsuwadee, Vore, Butterfield, & Clair, 2007; Conklin, 2004;
Tomar et al., 2017).
5 | CURCUMIN AS ANANTI ‐ INFLAMMATORY AGENT
Curcumin has been traditionally used for the treatment of several
inflammatory diseases (Aggarwal, Sundaram, Malani, & Ichikawa,
2007). These traditional applications have been translated in
modern pharmacological studies and randomized controlled trials
against a variety of human diseases including cancer (Iranshahi
et al., 2010; Mirzaei et al., 2016; Momtazi et al., 2016; Rezaee,
Momtazi, Monemi, & Sahebkar, 2017), respiratory diseases (Lelli,
Sahebkar, Johnston, & Pedone, 2017; Panahi, Ghanei, Bashiri,
Hajihashemi, & Sahebkar, 2014; Panahi, Ghanei, Hajhashemi, &
Sahebkar, 2016), osteoarthritis (Panahi, Alishiri, Parvin, & Sahebkar,
2016; Panahi, Rahimnia, et al., 2014; Sahebkar & Henrotin, 2016),
nonalcoholic fatty liver disease (Panahi, Kianpour, et al., 2016;
Rahmani et al., 2016; Zabihi, Pirro, Johnston, & Sahebkar, 2017),
and dyslipidemia (Cicero et al., 2017; Ganjali et al., 2017; Panahi,
Kianpour, et al., 2016). In the recent decades, biological studies
showed that it can affect more than 90 inflammatory targets in cells
(H. Zhou, Beevers, & Huang, 2011). Evidence show that curcumin is
able to attenuate the expression of some transcription factors
especially NF‐κB that has a central role for regulation of inflamma-
tion (Shehzad, Rehman, & Lee, 2013). Also, it can attenuate the
metabolism of prostaglandins and lipoxygenases, which are involved
in appearance of inflammatory signs and also lead to production of
free radicals (Aggarwal & Harikumar, 2009). iNOS is another target
for curcumin that it induces nitrative DNA damage and attenuation
of DNA damage response through nitroacetylation of 8‐oxoguanine‐DNA glycosylase 1 (Ogg1), an important modulator of base excision
repair pathway (Onoda & Inano, 2000). Curcumin through inhibition
of inflammatory cytokines such as IL‐1 and TNF‐α can prevent from
several inflammatory diseases (Aggarwal & Harikumar, 2009). Also,
it has antioxidant effects that prevents oxidative damage and
carcinogenesis (López‐Lázaro, 2008). Daily treatment with curcumin
has shown that can reverse reduction of bone marrow cells in
carcinoma‐bearing mice. Curcumin is able to reduces tumor‐inducedhepatic injury, and also is able to reverse reduction of hematopoie-
tic parameters such as total count of immune cells like lymphocytes
(Pal et al., 2005).
6 | PROTECTION AGAINSTINFLAMMATION IN RESPONSETO RADIATION AND CHEMOTHERAPYAGENTS: EXPERIMENTAL STUDIES
As mentioned, inflammation is originated form DNA damage and cell
death, especially necrosis, which is a common type of cell death in
radiotherapy and chemotherapy. It is confirmed that inflammatory
responses to cancer therapy may lead to chronic oxidative stress,
which may lead to damage to the normal function of organs. Also, it
may cause accumulation of unrepaired DNA damage, leading to
genomic instability and cancer (Najafi, Motevaseli, et al., 2018).
Inflammation can induce reduction–oxidation reactions, which itself
play a key role in triggering of inflammation responses. A positive
feedback between inflammation and redox responses lead to some
late side effects such as dermatitis, mucositis, enteritis, pneumonitis,
cardiac injury, and other (Yahyapour, Motevaseli, et al., 2018). As
curcumin has both antioxidant and anti‐inflammation properties, it
has proposed for preventing and treatment of various types of
inflammatory diseases in cancer radiotherapy and chemotherapy
(Verma, 2016).
6.1 | Bone marrow toxicity
Bone‐marrow stem cells are among the most sensitive cells to
ionizing radiation and chemotherapy drugs within the human body
(Wang et al., 2010). Studies have proposed that activation of some
cytokines and proapoptosis pathways are involved in high toxicity of
bone marrow cells to cancer therapy agents (Wang et al., 2010).
Exposure of bone marrow cells to ionizing radiation lead to a
significant increase in the apoptosis induction during some hours
(Meng, Wang, Brown, Van Zant, & Zhou, 2003). This is associated
with elevation of TGF‐β secretion, which can continue for long time
after exposure (Zhang et al., 2013). Chronic upregulation of TGF‐β is
associated with continuous production of ROS and NO by macro-
phages and lymphocytes, as well as some other cells (Anscher, 2010).
TGF‐β through stimulation of some ROS producing enzymes such as
nicotinamide adenine dinucleotide phosphate oxidase, and also via
upregulation of iNOS induces oxidative and nitrative damages in
bone marrow cells (Wang et al., 2010). The redox interactions
between immune mediators and ROS/NO‐producing enzymes may
continue for some weeks after exposure to radiation (Paraswani,
Ghosh, & Thoh, 2017). Bone marrow toxicity also has observed after
treatment with various chemotherapy agents such as cisplatin,
carboplatinum, busulfan (BU), 5‐fluorouracil (5‐FU), cyclophospha-mide, and other (Newman et al., 2016). In addition to oxidative injury,
these drugs may lead to apoptosis, senescence, and activation of
redox interactions (Hassanshahi, Hassanshahi, Khabbazi, Su, &
Xian, 2017).
Curcumin has been shown is able to protect bone marrow cells
against toxic effects of radiation and chemotherapy. X. Chen et al.
showed that curcumin can induce activity of some DNA repair
enzymes and attenuates myelosuppression following injection of
4 | FARHOOD ET AL.
carboplatin to mice. Results indicated an increase in the expression of
BRCA1, BRCA2, and ERCC1 in the mice bone marrow cells in a
curcumin dose dependent manner. This was associated with
reduction of DNA damage in bone marrow cells (X. Chen et al.,
2017). Curcumin also reduces chromosome aberrations in rats bone
marrow cells following cisplatin injection (Antunes, Araújo, Darin, &
Bianchi, 2000). Zhou et al. showed that combination of curcumin and
mitomycin C reduces the side effects of mitomycin C on bone
marrow cells. They showed that curcumin through inhibition of
glucose regulatory protein (GRP58), a protein which mediate
mitomycin DNA cross link, reduces DNA damage and subsequent
toxicities in bone marrow cells. They showed that inhibition of
GRP58 by curcumin is mediate through extracellular signal‐regulatedkinase (ERK)/p38 MAPK pathway (Q. M. Zhou, Zhang, Lu, Wang, &
Su, 2009).
6.2 | Dermatitis
Dermatitis induced by ionizing radiation is resulting from massive
apoptosis and necrosis of basal cells in derma. These lead to complex‐signaling pathways that lead to appearance of dermatitis with signs
such as redness, pain, dry desquamation, moist desquamation, dry
crusting, ulcers, and so forth. Studies have shown that upregulation
of various inflammatory mediators such as COX‐2, NF‐κB and
inflammasome, cytokines such as IL‐1, IL‐6, IL‐8, TNF‐α, and TGF‐β,and also infiltration of mast cells and T cells are involved in
appearance of dermatitis following exposure to ionizing radiation
(J.‐S. Kim et al., 2015; J. H. Lee et al., 2009; Müller & Meineke, 2007).
Curcumin has shown promising effects for mitigation of radiation‐induced skin injury (Jagetia & Rajanikant, 2005). Okunieff et al.
evaluated protective effect of curcumin on radiation‐induced skin
toxicity in mice. They irradiated hind part of mice legs with a single
50 Gy radiation and treated mice with 50, 100, or 200mg/kg
curcumin before and after irradiation. Skin toxicity were evaluated
during 2–3 weeks for evaluating acute dermatitis, and 90 days after
irradiation for chronic skin damage. Results showed that adminis-
tration of 200mg/kg curcumin can attenuate pathological appear-
ance of dermatitis in both times. Also, results indicated that
amelioration of dermatitis was related to suppression of IL‐1β,IL‐1Ra1, IL‐6, and IL‐18 (Okunieff et al., 2006). Kim et al. used a
cream containing curcumin at 200mg/cm2 in a mini‐pig model. Pigs
were irradiated locally with 50 Gy cobalt‐60 γ rays and then treated
with cream containing curcumin twice daily for 35 days. Results
showed a significant improvement in wound healing associated with
suppression of COX‐2 and NF‐κB (J. Kim et al., 2016).
6.3 | Mucositis
Mucositis is one of the most common side effects of radiotherapy,
which affects the mucosa. This complication may appear in oral for
head and neck cancers, and also in the gastrointestinal system. This
complication may appear as acute inflammation, pain, and ulceration
(Peterson, Bensadoun, Roila, & On behalf of the EGWG, 2011;
Ps, Balan, Sankar, & Bose, 2009). So far, some experimental studies
have conducted to evaluate protective effect of curcumin against
radiation‐induced mucositis. Rezvani et al. showed that treatment of
rats with curcumin reduces oral mucositis with a dose reduction factor
equal to 9%. Rats received curcumin at 200mg·kg−1·day−1 following
irradiation with 13.5–18Gy radiation (Rezvani & Ross, 2004).
Inhibition of inflammatory mediators such as NF‐κB and protein
kinase B (Akt) has proposed for protective effect of curcumin in the
intestine. In an animal study Rafiee et al. showed that a low dose of
ionizing radiation (1–5Gy) cause upregulation of NF‐κB and PI3K/Akt
pathways in human intestinal microvascular endothelial cells. Also,
they showed that treatment of rats with curcumin can attenuate
edema in endothelial cells. However, irradiation or curcumin treatment
did not cause any effect on regulation of mouse double minute 2
homolog (MDM2; Rafiee et al., 2010). Administration of curcumin
45mg·kg−1·day−1 for 2 weeks before irradiation has shown can
attenuate histopathological damages such as oxidative injury and
accumulation of fibroblasts (El‐Tahawy, 2009). Similar results were
obtained by another study by Fukuda et al. (2016).
6.4 | Pneumonitis and lung fibrosis
Pneumonitis in the lung is resulting from chronic upregulation several
inflammatory mediators, chemokines and cytokines, and transcrip-
tion factors. These lead to the accumulation of inflammatory cells
such as macrophages, mast cells, and lymphocytes. Interactions
between inflammatory cytokines with macrophages and lymphocytes
cause the continuous production of free radicals, including ROS and
NO. chronic oxidative stress following inflammatory responses
stimulate upregulation of profibrotic cytokines such as TGF‐β, andalso growth factors such as epithelial growth factor receptor (EGFR),
connective tissue growth factor (CTGF) and platelet‐derived growth
factor. Pneumonitis appears some months after radiotherapy, while
fibrosis may appear years later (Proklou, Diamantaki, Pediaditis, &
Kondili, 2018).
Curcumin as a potent immune modulator agent has shown is
able to modulate radiation responses in the lung tissue. Lee et al. in
an experimental study evaluated the radioprotective effect of
curcumin on oxidative injury and fibrosis in the mice lung tissue.
Mice were treated with a diet containing 5% curcumin for 2 weeks
and then irradiated with 13.5 Gy X‐ray. Results showed that
treatment with curcumin attenuate production of ROS by
pulmonary endothelial cells following irradiation. Also, curcumin
diet caused significant reduction of fibrosis and increased survival,
while it could not ameliorate pneumonitis (J. C. Lee et al., 2010). In
another study has been used from 200 mg/kg curcumin before to 8
weeks after irradiation. Results showed that curcumin treatment
can attenuate the upregulation of profibrotic genes including
TGF‐β1 and CTGF, alleviate inflammatory mediators including
TNFR1 and COX‐2, and also suppresses NF‐κB. These were
associated with attenuation of inflammatory cells accumulation,
edema, alveolar and vascular injury, as well as collagen deposition
(Cho et al., 2013).
FARHOOD ET AL. | 5
7 | ANTI ‐ INFLAMMATORY EFFECTOF CURCUMIN ON CANCER
Curcumin can induce apoptosis in some cancerous cells (Noorafshan
& Ashkani‐Esfahani, 2013). Treatment of human prostate cancer cell
line LNCaP with curcumin can induce apoptosis through upregulation
of proapoptosis genes (Deeb et al., 2003). Similarity, curcumin can
induce apoptosis in HepG2 cells, which it seems is resulting from
effects on mitochondrial function and increased superoxide produc-
tion (Cao et al., 2007). In addition to death signal pathways, curcumin
has shown that can attenuate inflammatory cytokines, which are
involved in the proliferation and differentiation of cancer stem cells.
Curcumin has shown that through suppression of some transcription
factors such as activator protein‐1, NF‐κB and STAT‐3, phosphodies-terases, some cytokines such as IL‐1, IL‐6, IL‐8, and also chemokine
receptors such as CXCR1 and CXCR2 can suppress differentiation of
cancer stem cells (Abusnina et al., 2015; C. Chen, Liu, Chen, & Xu,
2011; Deguchi, 2015; Sordillo & Helson, 2015; Teymouri, Barati,
Pirro, & Sahebkar, 2018). Suppression of Wnt/β‐catenin and Sonic
hedgehog pathways, and also some microRNAs by curcumin can
suppress cancer stem cells (Y. Li & Zhang, 2014; Zhu et al., 2017).
Curcumin has an inhibitory effect on angiogenesis and metastasis
factors such as angiopoetin‐1 and VEGF, and also matrix metallo-
proteinase‐3 (MMP‐3) that may be useful for suppression of tumor
growth (Boonrao, Yodkeeree, Ampasavate, Anuchapreeda, & Lim-
trakul, 2010; W. Li et al., 2018; Qadir et al., 2016; Ramezani,
Hatamipour, & Sahebkar, 2018; Saberi‐Karimian et al., 2017; Shakeri,
Ward, Panahi, & Sahebkar, 2018; You et al., 2017).
7.1 | Synergistic effect of curcumin with radiation
In addition to protection of normal tissues, sensitization of tumor
cells can cause decreases in demanded radiation dose, so as to
reduce the risk of normal tissues reactions and also secondary cancer
risk especially in the young people. So far, some agents have used for
sensitization of tumor cells to radiotherapy. However, severe toxicity
of these agents may lead to several side effects for patients. It has
been proposed that targeting of inflammation can attenuate normal
tissues injury, as well as sensitize tumor cells to ionizing radiation. On
the other hand, potent anti‐inflammation properties of curcumin can
be proposed for radiosensitization and radioprotection. As men-
tioned, curcumin is able to suppress several inflammation mediators
that are activated following exposure to ionizing radiation. As some
of inflammatory mediators are able to induce angiogenesis and
proliferation of cancer cells, inhibition of them by curcumin can
attenuate tumor cells growth and repopulation during radiotherapy
(Verma, 2016).
Curcumin has shown is able to sensitize cancer cells to ionizing
radiation through induction of proapoptosis and attenuation and
antiapoptosis genes. Qiao et al. showed that curcumin reduces the
expression of NF‐κB in human Burkitt’s lymphoma cells, leading to
increasing apoptosis induction in these cells. They showed that PI3K/
Akt pathway inhibition by curcumin is responsible for attenuation of
NF‐κB regulation (Qiao, Jiang, & Li, 2013). This was associated with
cell cycle arrest in G2‐M, which is more sensitive to kill by ionizing
radiation (Calaf, Echiburu‐Chau, Wen, Balajee, & Roy, 2012; Qiao,
Jiang, & Li, 2012). Similar results were obtained for nasopharyngeal
carcinoma (Pan et al., 2013).
Suppression of NF‐κB by curcumin has shown attenuate down-
stream genes such as COX‐2 and VEGF, which cause inhibition of
tumor growth. A study showed that treatment of tumor‐bearing mice
with curcumin that were exposed to radiation lead to 50% reduction
in COX‐2 and VEGF, and remarkable tumor regrowth delay in
xenograft colorectal cancer (Kunnumakkara et al., 2008). Similar
results were observed for HepG2, rhabdomyosarcoma, human oral
squamous cell carcinoma, and breast cancer cells (Chiang et al., 2014;
Gallardo & Calaf, 2016; Hsu, Liu, Liu, & Hwang, 2015; Orr et al.,
2013). In addition to inhibition of angiogenesis factors, curcumin has
shown attenuate telomerase activity, which itself is depend to NF‐κBactivity. Combination of curcumin with radiation has shown that
reduces the expression of telomerase reverse transcriptase (TERT)
gene in human neuroblastoma cells (Aravindan, Veeraraghavan,
Madhusoodhanan, Herman, & Natarajan, 2011). This property can
reduce survival of irradiated cells. Chendil, Ranga, Meigooni,
Sathishkumar, and Ahmed (2004) proposed that inhibitory effect of
curcumin on TNF‐α is involved in NF‐κB suppression and radio-
sensitization of PC3 cells. Also, in response to radiation, curcumin is
able to phosphorylate IkB directly, an inhibitor of NF‐κB (Orr et al.,
2013; Sandur et al., 2009). Inhibition of EGFR is another mechanism
for curcumin that may be involved in radiosensitization of cancer
cells (Khafif et al., 2009). Also, it is proposed that curcumin through
upregulation of ERK1/2 amplifies the production of ROS following
exposure of cancer cells to radiation (Javvadi, Segan, Tuttle, &
Koumenis, 2008).
Curcumin has shown that through inhibition of PI3K suppresses
the regulation of MDM2, a suppresser of p53. Suppression of MDM2
can increase activity of p53, which is necessary for initiation of
apoptosis in cancerous cells. Curcumin through modulation of this
pathway has shown sensitize PC3 cells to ionizing radiation and
chemotherapy (M. Li, Zhang, Hill, Wang, & Zhang, 2007). These
results were confirmed by Veeraraghavan, Natarajan, Herman, and
Aravindan (2010), which showed that curcumin induces apoptosis in
sarcoma cells through modulation of p53 and other related genes
such as p21 and Bax.
7.2 | Synergistic effect of curcumin withchemotherapy drugs
Several in vitro, animal and clinical studies have shown that curcumin
has a synergistic effect with some chemotherapy agents such as
bevacizumab, 5‐FU, and oxaliplatin (FOLOX; Anitha, Deepa, Chennazhi,
Lakshmanan, & Jayakumar, 2014; Anitha, Sreeranganathan, Chennazhi,
Lakshmanan, & Jayakumar, 2014; Irving et al., 2015; James et al., 2015;
Yue et al., 2016). Combination of curcumin with chemotherapy drugs
has shown is able to attenuate inflammation and oxidative signs
associated with tumor growth (Marjaneh et al., 2018). Sen et al. showed
6 | FARHOOD ET AL.
that curcumin through targeting of NF‐κB help to antitumor effect of an
adjuvant chemotherapeutic drug. This study showed doxorubicin cause
degradation of Iκbα, leading to activation of NF‐κB and resistance of
Ehrlich ascites carcinoma cells, which injected to mice. Treatment of
mice with 50mg/kg curcumin lead to significant reduction of tumor
cells viability. This was associated with inhibition of nuclear transloca-
tion of NF‐κB and suppression of B‐cell lymphoma 2 (Bcl‐2), as well as,
induction of proapoptosis genes such as p53, Bax, p53 upregulated
modulator of apoptosis (PUMA), and phorbol‐12‐myristate‐13‐acetate‐induced protein 1 (NOXA) (Sen et al., 2011). Another study by Yang
et al. (2017) showed that inhibition of NF‐κB and COX‐2 by curcumin
enhance the cytotoxic effect of 5‐FU against gastric cancer MKN45 and
AGS cells. Similar results showed for esophageal squamous cell
carcinoma, breast, and colorectal cancer cells (Shakibaei et al., 2013;
Tian, Fan, Zhang, Jiang, & Zhang, 2012; Vinod et al., 2013). It is
confirmed that NF‐κB mediate tumor resistance through upregulation
of antiapoptosis factors, including Bcl‐2 (Bava et al., 2011).
In addition to NF‐κB, curcumin combination with chemotherapy
drugs has shown is able to sensitizes cells through inhibition growth
factors. VEGF and EGFR are important genes that play a central role
in tumor growth. However, it seems that regulation of these growth
factors are highly depend to NF‐κB too. Curcumin has shown inhibits
VEGF, ICAM‐1, MMP‐9, and other inflammatory mediators in
colorectal cancer cells in response to capecitabine (Kunnumakkara
et al., 2009). Another study showed that curcumin in combination of
5‐FU and doxorubicin through inhibition of EGFR‐ERK1/2 signaling
can attenuate proliferation of head and neck squamous cell
carcinoma (Sivanantham, Sethuraman, & Krishnan, 2016).
8 | WHAT IS THE EVIDENCE FROMCLINICAL TRIALS?
In addition to experimental studies, some clinical trials showed that
curcumin can be proposed for amelioration of side effects of cancer
therapy such as inflammatory disorders. Dermatitis and mucositis are
two inflammatory side effects of cancer therapy that proposed as
target diseases for curcumin. Dermatitis is one the most common
side effects of radiotherapy for different types of cancers. It is
estimated that 95% patients with breast cancer that undergo
radiotherapy show signs of dermatitis. Palatty et al. evaluated
possible protective effect of a cream containing curcumin and sandal
wood oil for patients with head and neck cancer that undergo
radiotherapy. The first pilot study showed promising results. They
showed that this cream can alleviate Grade 3 of dermatitis of
radiotherapy patients (Palatty et al., 2014). Using this cream showed
that it is able to reduce signs of dermatitis during Weeks 2 and 3.
Patients in this study received a total dose equal 50 Gy (2 Gy/day,
five times per week) for 5 consecutive weeks (Rao et al., 2017). Ryan
et al. (2013) evaluated therapeutic effect of curcumin on radiation‐induced dermatitis in a double‐blind clinical trial study including
30 patients with breast cancer. Patients received 6 g daily curcumin
or placebo as orally during course of radiotherapy. Results showed TABLE
1Su
mmaryofstudiesreportingan
ti‐in
flam
matory
effectsofcu
rcumin
innorm
alcells
Route/ce
lllin
eTarge
tModality
Dosage
/durationofcu
rcumin
Majorfindings
Referen
ces
Mice
Bonemarrow
Chem
otherap
y(carboplatin)
0.1ml5mM·m
ouse
−1·day
−1
Atten
uation
ofchromosom
eab
erration
san
dmyelosupp
ression,
andup
regu
lation
ofBRCA1,B
RCA2,and
ERCC1
(Chen
etal.,2017)
Rat
Bonemarrow
Chem
otherap
y(cisplatin)
8mg/kg
for2day
sRed
uctionofch
romosomeab
errations
(Antunes
etal.,2000)
Mice
Bonemarrow
Chem
otherap
y(m
itomycin
C)
100mg/kg
for4wee
ksInhibitingDNA
cross‐linking
(Zhouet
al.,2009)
Mice
Lung
Rad
iation
5%
indietstartingfrom
2
wee
ksbefore
Red
uctionofROSproductionbyen
dothelialcells,
attenuationofinflam
mationan
dfibrosis
(Lee
etal.,2010)
Rats
Tongu
esRad
iation
200mg·kg
−1·day
−1foren
dof
study
Red
uctionofmuco
sitisby9%
(Rezva
nian
d
Ross,2
004)
Invitro,
rat
Human
intestinal
microva
scular
endothelialcells/ratsintestine
Rad
iation
10μM
,2%
ofdaily
diet
Atten
uationofNF‐κBan
dPI3K/A
kt/m
TORsign
aling,
alleviationofed
emain
endothelialcells
(Rafieeet
al.,2010)
Mice
Intestine
Rad
iation
0.5%
(wt/wt)
Red
uctionofap
optosis,increa
sednumbersofvilli
(Fuku
daet
al.,2016)
Mice
legs
Rad
iation
200mg/kg
Atten
uationofdermatitis,suppressionofinflam
matory
cytokines
includingIL‐1β,
IL‐1Ra1
,IL‐6,an
dIL‐18
(Oku
nieffet
al.,2006)
Pig
Rad
iation
Curcumin
crea
mat
200mg/
cm2tw
icedaily
for35day
s
Improve
men
tin
woundhea
ling,
inhibitionofCOX‐2
and
NF‐κB
(Kim
etal.,2016)
Note.Akt:p
rotein
kinaseB;C
OX‐2:cyclooxy
genase‐2;IL‐1β:
interleu
kin‐1β;
NF‐κB:n
uclea
rfactorκB
;PI3K:p
hosphoinositide3‐kinase;
mTOR:m
ammaliantarget
ofrapam
ycin;R
OS:
reactive
oxy
genspecies.
FARHOOD ET AL. | 7
that curcumin administration do not able to attenuate redness but it
causes significant reduction of dermatitis and moist desquamation.
However, reduction of dermatitis was observed after fifth weeks
(Ryan et al., 2013). Another clinical trial study on 686 patients
showed that administration of 2 g/day cannot attenuate dermatitis in
breast cancer patients that undergo radiotherapy (Ryan Wolf et al.,
2018). It seems that the main difference between these studies is
resulting from dose of curcumin that patients received.
In a pilot study comprising 20 patients with cancer who
underwent radiochemotherapy, the efficacy of curcumin in amelior-
ating oral mucositis was tested. Results showed that administration
of curcumin attenuated mucositis and improved wound healing (Patil,
Guledgud, Kulkarni, Keshari, & Tayal, 2015). Curcumin also attenu-
ated chemotherapy‐induced mucositis in pediatric patients (Elad
et al., 2013). In a clinical study comprising >200 patients with head
and neck cancers, the incidence of mucositis following chemora-
diotherapy with or without curcumin treatment was evaluated.
Administration of curcumin was started 3 days before radiotherapy
at a dose of 2 g/day, and was continued for 3 months. Curcumin
treatment delayed the initiation of mucositis by 7 days and reduced
mean duration of it by 20 days. The most obvious reduction of
mucositis duration was for Grades 3 and 4 by 22 days. Moreover,
treatment with curcumin reduced the incidence of mucositis from
89% to 51% (Adhvaryu & Reddy, 2018). In another study by Rao et al.
the efficacy of curcumin in reducing mucositis in patients with head
and neck cancer who underwent radiotherapy or radiochemotherapy
was evaluated. Patients were visited each week for a 7‐week follow‐up. Patients who received chemoradiation first received carboplatin
(1 dose/week). Radiotherapy was planned to provide 70Gy radiation
dose to tumor. Patients received a solution containing 300mg
curcumin at 6 doses/day during the treatment course. Results
showed that radiotherapy caused a significant mucositis from the
first week to the end of radiotherapy. Treatment with curcumin
showed delayed and reduced mucositis at all weeks (Rao et al., 2014).
9 | CONCLUSION
As mentioned in the above sections, curcumin possesses interesting
properties for the amelioration of inflammatory complications of
radiotherapy and chemotherapy. Inflammation is involved in acute
reactions to ionizing radiation and also chemotherapy drugs in
various organs such as bone marrow, lung, heart, and gastrointestinal
system. In addition to toxic effects on normal tissues, a large number
of studies have revealed pivotal role of inflammatory mediators in
tumor resistance and decreased efficiency of chemotherapy. Inflam-
mation can induce chronic upregulation of several cytokines and
continuous production of free radicals, leading to genomic instability,
pain, ulcer, and fibrosis. Curcumin is a nontoxic dietary polyphenol
that is able to target a large number of inflammatory mediators. It
seems that several therapeutic effects of curcumin are mediated
through modulation of NF‐κB. Targeting of NF‐κB by curcumin
attenuates the release of inflammatory cytokines, prostaglandins,TABLE
2Su
mmaryofstudiesreportingan
ti‐in
flam
matory
effectsofcu
rcumin
against
cancercells
Tumorce
llsModality
Majorfindings
Mec
han
isms
Referen
ce
Human
Burkitt’slymphomacells
Rad
iation
Apoptosisinduction
NF‐κBan
dPI3K/A
ktpathway
inhibition
(Qiaoet
al.,2013)
Human
Burkitt’slymphomacells
Rad
iation
Apoptosisinduction
Increa
sedG2/M
phasearrest
andNF‐κBinhibition
(Qiaoet
al.,2012)
MCF‐10F
Rad
iation
Proliferationsuppression,g
rowth
inhibition
Increa
sedG2/M
phasearrest,red
uctionofRasGRF1
expression,a
ndincrea
singDNA
dam
age
Calaf
etal.(2012)
PC3cells
Rad
iation
Apoptosisinduction
InhibitionofPI3K
andactiva
tionofp53
(Liet
al.,2007)
Sarcomacells
Rad
iation
Apoptosisinduction
Stim
ulationofp53,p
21,a
ndBax
(Vee
raragh
avan
etal.,2010)
Nasopharyn
geal
carcinoma
Rad
iation
Inhibitionoftumorgrowth,a
poptosisinduction
Inactiva
tionofJab1,G2/M
arrest
(Pan
etal.,2013)
Ehrlichascitescarcinomacells
Doxo
rubicin
Red
uctionoftumorcells
viab
ility
SuppressionofNF‐κBan
dBcl‐2,activa
tionofp53,
Bax
,PUMA,a
ndNOXA
(Sen
etal.,2011)
MKN45an
dAGScells
5‐FU
Inhibitionoftumorgrowth
InhibitionofNF‐κBan
dCOX‐2
(Yan
get
al.,2017)
HCT116an
dch
3cells
5‐FU
Apoptosisinduction
Mitoch
ondrial
deg
enerationan
dupregu
lationof
proap
optoticproteins
(Shak
ibae
i
etal.2
013)
HNSC
C5‐FU
andDOX
Apoptosisinduction,g
rowth
inhibition
Cellcyclegrowth
arrest
attheG1/S
phase,
increa
sed
p21,p
53,a
ndBax
(Sivan
antham
et
al.,2016)
Note.
Akt:protein
kinaseB;EAC:Ehrlichascitescarcinoma;
5‐FU:5‐fluorouracil;HNSC
C:hea
dan
dnecksquam
ouscellcarcinoma;
PI3K:phosphoinositide3‐kinase;
NF‐κB:nuclea
rfactorκB
.
8 | FARHOOD ET AL.
pro‐oxidant enzymes and free radicals. These effects reduce damage
to DNA and cell death, leading to the attenuation of redox
interactions and chronic oxidative stress. As NF‐κB has a potent
antiapoptotic activity, targeting of NF‐κB by curcumin in tumor cells
sensitizes the cells to apoptosis, thereby reducing cell survival and
tumor growth. Upregulation of proapoptotic factors such as p53 and
Bax, and arrest of cell cycle in G1 or G2 phases are other antitumor
activities of curcumin that enhance the toxic effects of radiation and
chemotherapy agents on tumor cells. Although clinical studies of
curcumin administration in patients with cancer are limited, some
studies have proposed beneficial effects of this phytochemical in
reducing dermatitis and mucositis. However, additional robust
evidence is still required from proof‐of‐concept trials in patients
with cancer to determine the role of curcumin in preventing
chemotherapy‐ and radiotherapy‐induced inflammatory complica-
tions as well as the optimal dosing and formulation of curcumin to
elicit pharmacological effects (Table 1,2).
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
ORCID
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
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How to cite this article: Farhood B, Mortezaee K, Goradel
NH, et al. Curcumin as an anti‐inflammatory agent:
Implications to radiotherapy and chemotherapy. J Cell Physiol.
2018;1‐13. https://doi.org/10.1002/jcp.27442
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