Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy
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.
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 chemotherapy 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 outcome 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 catastrophe, 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 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 TISSUES FOLLOWING 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-induced inflammation 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). These cytokines 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 TISSUES FOLLOWING 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 downstream 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-3 pathway is involved in cisplatin nephrotoxicity. Suppression of this mediators showed that attenuate cisplatin-induced nephrotoxicity (Arjumand, Seth, & Sultana, 2011). In addition, it is proposed that cisplatin through stimulation of COX-2 upregulation 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, & Abdelrahman, 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 inflammasome 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 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 AN ANTI-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 inflammation (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-induced hepatic injury, and also is able to reverse reduction of hematopoietic parameters such as total count of immune cells like lymphocytes (Pal et al., 2005).
6 PROTECTION AGAINST INFLAMMATION IN RESPONSE TO RADIATION AND CHEMOTHERAPY AGENTS: 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 macrophages 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), cyclophosphamide, 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 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-regulated kinase (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 200 mg/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 administration of 200 mg/kg curcumin can attenuate pathological appearance 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 200 mg/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 200 mg·kg−1·day−1 following irradiation with 13.5–18 Gy 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 (1–5 Gy) 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 45 mg·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 transcription 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, and also 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).
7 ANTI-INFLAMMATORY EFFECT OF 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 production (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, phosphodiesterases, 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 metalloproteinase-3 (MMP-3) that may be useful for suppression of tumor growth (Boonrao, Yodkeeree, Ampasavate, Anuchapreeda, & Limtrakul, 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 mentioned, 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 downstream 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-κB activity. 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 radiosensitization 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 with chemotherapy 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 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 50 mg/kg curcumin lead to significant reduction of tumor cells viability. This was associated with inhibition of nuclear translocation 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 FROM CLINICAL 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 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 ameliorating oral mucositis was tested. Results showed that administration of curcumin attenuated mucositis and improved wound healing (Patil, Guledgud, Kulkarni, Keshari, & Tayal, 2015). Curcumin also attenuated 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 chemoradiotherapy 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 70 Gy radiation dose to tumor. Patients received a solution containing 300 mg 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. Inflammation 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, 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 complications as well as the optimal dosing and formulation of curcumin to elicit pharmacological effects (Table 1, 2).
| Route/ cell line | Target | Modality | Dosage/duration of curcumin | Major findings | References |
|---|---|---|---|---|---|
| Mice | Bone marrow | Chemotherapy (carboplatin) | 0.1 ml 5 mM·mouse−1·day−1 | Attenuation of chromosome aberrations and myelosuppression, and upregulation of BRCA1, BRCA2, and ERCC1 | (Chen et al., 2017) |
| Rat | Bone marrow | Chemotherapy (cisplatin) | 8 mg/kg for 2 days | Reduction of chromosome aberrations | (Antunes et al., 2000) |
| Mice | Bone marrow | Chemotherapy (mitomycin C) | 100 mg/kg for 4 weeks | Inhibiting DNA cross-linking | (Zhou et al., 2009) |
| Mice | Lung | Radiation | 5% in diet starting from 2 weeks before | Reduction of ROS production by endothelial cells, attenuation of inflammation and fibrosis | (Lee et al., 2010) |
| Rats | Tongues | Radiation | 200 mg·kg−1·day−1 for end of study | Reduction of mucositis by 9% | (Rezvani and Ross, 2004) |
| In vitro, rat | Human intestinal microvascular endothelial cells/rats intestine | Radiation | 10 μM, 2% of daily diet | Attenuation of NF-κB and PI3K/Akt/mTOR signaling, alleviation of edema in endothelial cells | (Rafiee et al., 2010) |
| Mice | Intestine | Radiation | 0.5% (wt/wt) | Reduction of apoptosis, increased numbers of villi | (Fukuda et al., 2016) |
| Mice | legs | Radiation | 200 mg/kg | Attenuation of dermatitis, suppression of inflammatory cytokines including IL-1β, IL-1Ra1, IL-6, and IL-18 | (Okunieff et al., 2006) |
| Pig | Radiation | Curcumin cream at 200 mg/cm2 twice daily for 35 days | Improvement in wound healing, inhibition of COX-2 and NF-κB | (Kim et al., 2016) |
- Note. Akt: protein kinase B; COX-2: cyclooxygenase-2; IL-1β: interleukin-1β; NF-κB: nuclear factor κB; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; ROS: reactive oxygen species.
| Tumor cells | Modality | Major findings | Mechanisms | Reference |
|---|---|---|---|---|
| Human Burkitt's lymphoma cells | Radiation | Apoptosis induction | NF-κB and PI3K/Akt pathway inhibition | (Qiao et al., 2013) |
| Human Burkitt's lymphoma cells | Radiation | Apoptosis induction | Increased G2/M phase arrest and NF-κB inhibition | (Qiao et al., 2012) |
| MCF-10F | Radiation | Proliferation suppression, growth inhibition | Increased G2/M phase arrest, reduction of RasGRF1 expression, and increasing DNA damage | Calaf et al. (2012) |
| PC3 cells | Radiation | Apoptosis induction | Inhibition of PI3K and activation of p53 | (Li et al., 2007) |
| Sarcoma cells | Radiation | Apoptosis induction | Stimulation of p53, p21, and Bax | (Veeraraghavan et al., 2010) |
| Nasopharyngeal carcinoma | Radiation | Inhibition of tumor growth, apoptosis induction | Inactivation of Jab1, G2/M arrest | (Pan et al., 2013) |
| Ehrlich ascites carcinoma cells | Doxorubicin | Reduction of tumor cells viability | Suppression of NF-κB and Bcl-2, activation of p53, Bax, PUMA, and NOXA | (Sen et al., 2011) |
| MKN45 and AGS cells | 5-FU | Inhibition of tumor growth | Inhibition of NF-κB and COX-2 | (Yang et al., 2017) |
| HCT116 and ch3 cells | 5-FU | Apoptosis induction | Mitochondrial degeneration and upregulation of proapoptotic proteins | (Shakibaei et al. 2013) |
| HNSCC | 5-FU and DOX | Apoptosis induction, growth inhibition | Cell cycle growth arrest at the G1/S phase, increased p21, p53, and Bax | (Sivanantham et al., 2016) |
- Note. Akt: protein kinase B; EAC: Ehrlich ascites carcinoma; 5-FU: 5-fluorouracil; HNSCC: head and neck squamous cell carcinoma; PI3K: phosphoinositide 3-kinase; NF-κB: nuclear factor κB.
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
