INTRODUCTION
Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl) −1,6-heptadiene-3,5-dione, Figure 1a][1] is a major constituentof turmeric (Curcuma longa L.).[2] It is a hydrophobicpolyphenol and derived from the rhizome of turmeric [Figure 2]. Curcumin's molecular weight is 368.385 g/mol, and the molecular formula is C21H20O6. The yellow-colored compound curcumin is the most active curcuminoid present in turmeric. It is indicated as the “golden spice” in many Asian countries and has widely been used in many traditional medicines during the last 2500 years.[345]
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Figure 1: The chemical structures of important constituents present in turmeric: (a) curcumin (ChemSpider ID839564 2018); (b) demethoxycurcumin; and (c) bisdemethoxycurcumin
Figure 2: Turmeric fresh rhizome and powder
Turmeric is a common spice known for its anti-inflammatory properties and has been used in traditional medicine in India.[3678] The pharmacological activity of turmeric is mainly attributed to curcuminoids consisting of curcumin [Figure 1a] and two related compounds, namely dimethoxy curcumin [4-hydroxycinnamoyl-(4-hydroxy-3-methoxyc innamoyl) methane, Figure 1b][1] and bis-dimethoxy curcumin [bis-(4-hydroxycinnamoyl) methane, Figure 1c].[19] Curcumin is the main curcuminoid in turmeric and has been found to possess various beneficial properties, including anti-inflammatory,[10] antioxidant,[11] neuroprotective,[1213] chemopreventive, and chemotherapeutic[1415] activities, which make this phytocompound famous for characterized as “curecumin.”[16] Curcumin affects multiple signaling pathways involved in cell proliferation, survival, cell death, angiogenesis, invasion, migration, and metastasis.[17] Cancer preventive and anticancer therapeutic actions of curcumin against different types of cancers, such as breast, liver, melanoma, lung, and endometrium, are available in the literature.[1819202122] Besides, it is a free-radical scavenger and displays both pro- and antioxidant activities.[2324] Curcumin also exhibited limited bioavailability.[12141525] Based on clinical trials in cancer patients, it was concluded that even 8 g of curcumin was safe and well tolerated.[26]
As a therapeutic agent, curcumin has been subjected to clinical trials for various diseases, such as psoriasis,[27] multiple myeloma, chronic uveitis, pancreatitis, pancreatic, colorectal, and biliary tract cancers,[1428] familial adenomatous polyposis, inflammatory bowel disorder,[10] Alzheimer's disease,[13] and diabetes mellitus.[29] For a long time, there has been growing attention to a probable beneficial role of curcumin in cancer. It is essential to understand the mechanisms of action of curcumin and determine its effectiveness in cancer patients. Hence, clinical trials might lead to a broader acceptance for its use in cancer medicine. The purpose of this review is to analyze the results of cancer clinical trials of curcumin and turmeric published during the last decade (2010–2020).
METHODOLOGY FOR LITERATURE SEARCH
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria[30] have been followed for this work. Several mainstream scholarly databases, such as PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov, were used to find clinical trials published between 2010 and 2020. The last search was performed in June 2020. The keywords, such as “curcumin,” “cancer,” “anti-inflammatory,” and “clinical trials,” were used in various combinations. Only reports published in the English language were included. Book chapters, conference abstracts, and letters to editors were excluded.
RESULTS ON COMPLETED CLINICAL TRIALS OF CURCUMIN AND/OR TURMERIC IN CANCER
Various clinical trials investigated curcumin's bioavailability, its effect on various cancer types, and the efficacy of turmeric and curcumin in mitigating the side effects of cancer chemotherapy and radiotherapy [Table 1].
Table 1: Dosimetric results for the planned target volume, tumor control probability, and monitor unit for the field-in-field, three-field, and four-field (box) plans
The clinical trials related to the bioavailability of curcumin
Due to curcumin's low bioavailability, its clinical use has been limited.[3132] Therefore, several trials are designed to identify and improve the bioavailability of curcumin. Improving bioavailability, various curcumin analogs designed, and synthesized, novel drug delivery systems (e.g., phospholipids, nanoparticles, and liposomes) have been utilized.[33]
A randomized, double-blind placebo-controlled trial evaluated the efficacy of curcuminoids as adjuvant therapy in cancer patients. A phytosomal preparation of curcuminoids (Meriva®; Indena SpA, Italy) was used for the present study. In this trial, curcuminoid preparation remarkably improved health-related quality of life (QoL) score and suppressed systemic inflammation in patients with solid tumors under standard chemotherapy regimens. Forty patients with solid tumors, such as colorectal, gastric, breast, sarcoma, lymphoma, lung, prostate, and bladder tumors, were treated with a bioavailability-boosted curcuminoid preparation (180 mg/day), and 40 patients were subjected to placebo treatment for a period of 8 weeks. Efficacy measures were the changes in the health-related QoL score, and the score was evaluated using the University of Washington index. Multiple serum levels of a panel of mediators were measured to evaluate systemic inflammation. Curcuminoid supplementation was related to greater improvement in QoL compared with the placebo. Constantly, the reductions in transforming growth factor-β (TGF-β), tumor necrosis factor-α, interleukin-6, high-sensitivity C-reactive protein, substance P, calcitonin gene-related peptide, and monocyte chemotactic protein-1 were all remarkably greater in the group treated with the curcuminoids compared to the placebo group (PG). The grade of decrease in serum interleukin-8 was greater in the PG compared to the curcuminoid group. QoL variations were related to alterations of serum TGF-β levels. It was concluded that an additional group needs to receive unformulated curcuminoids to determine the extent of improvement in treatment response by Meriva®.[34]
In another study, a novel formulation of curcumin (Theracurmin®; nanoparticles containing curcumin extract from turmeric) was developed to improve curcumin's bioavailability. Theracurmin® is a highly bioavailable than other enhanced and regular forms of curcumin. It was administered for a single time, which resulted in elevated plasma curcumin levels in healthy volunteers. Repetitive administrations of Theracurmin® were evaluated in pancreatic or biliary duct cancer patients who did not respond to standard chemotherapy. Initially, Theracurmin® comprising 200 mg of curcumin was used, and the dose was increased to 400 mg of curcumin. Theracurmin® was given per os daily with standard gemcitabine-based chemotherapy. Any adverse events were noticed, and three patients continued Theracurmin® administration for more than 9 months. Recurrent systemic exposure to Theracurmin® did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.[28]
The clinical trials related to curcumin's effectiveness in several cancer types
Imatinib is one of the most preferred drugs in the treatment of chronic myeloid leukemia (CML). A clinical trial that was related to imatinib was conducted in 50 CML patients. The patients were divided into two groups: one group received imatinib (400 mg twice a day) alone, and the other group was treated with imatinib in addition to turmeric powder (5 g three times/day) for 6 weeks. Increased serum levels of nitric oxide (NO) have been reported in the group with a combined treatment with imatinib and turmeric powder as compared to imatinib therapy alone. In both the treatment groups, NO levels were significantly decreased, but the results were more pronounced than the group that received combined treatment. Therefore, the authors conclude that turmeric powder may act as an adjuvant in reducing NO levels and may be beneficial in the treatment of CML.[35]
According to a randomized, double-blind placebo-controlled crossover study, a 4-g dose of curcumin was administered followed by an open-label extension study using an 8-g dose to assess the effect of curcumin on free light-chain ratio response and bone turnover in patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Thirty-six patients were randomly divided into two groups. One group was given 4-g curcumin, and the other group was a placebo during 3 months of the study. Following the treatment with 4-g curcumin, all patients were given the option of entering into an open-label, 8-g dose extension study. The outcome of this study suggested that curcumin could have a positive effect on decelerating the disease process in patients with MGUS and SMM.[36]
Efficacy of docetaxel and curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC) was evaluated in a Phase II trial for 30 patients with progressing CRPC and an increasing prostate-specific antigen (PSA) who received docetaxel/prednisone for six cycles in combination with oral curcumin (6 mg per day). It was observed that the PSA level and objective response rate were not linked to the serum values of chromogranin A and neuron-specific enolase. The study generated novel data on curcumin's efficacy in treating cancer with a high response rate, well tolerability, and patient acceptability.[37]
A Phase I/II trial showed that curcumin was safe and tolerable. Inoperable metastatic colorectal cancer patients received oral curcumin with 12 cycles of 5-fluorouracil, folinic acid, and oxaliplatin chemotherapy regimen at doses up to 2 g daily. This study showed the effectiveness of this approach (NCT01490996).[38]
A Phase II single-group assignment open-label study was aimed to define if curcumin can inhibit tumor-induced inflammation in patients with endometrial carcinoma. Curcuphyt (C. longa root extract standardized at 100 mg curcuminoids) was used as a dietary supplement in seven patients. Curcuphyt capsules (2 g/day) were given for 2 weeks. Inflammatory biomarkers, frequency of immune cell types, T-cell activation, and cyclooxygenase-2 expression were not different in the Curcuphyt-treated group compared to control. A nonsignificant trend was observed for improved QoL. In general, Curcuphyt-induced immunomodulatory effects in endometrial carcinoma were moderate without significant QoL changes. Given the variability observed in the small population and interpatient biomarker levels, further research is needed to investigate whether Curcuphyt can benefit from different supplementary regimens in endometrial carcinoma.[3940]
Another Phase 1 study was conducted to evaluate curcumin's chemopreventive potential in colorectal neoplasia as well as its tolerability and toxicity. The researchers evaluated 40 patients following initial colonoscopy screening and analyzed rectal biopsy samples obtained after 4 weeks of curcumin (4 g daily) treatment. In future chemoprevention studies, microarray analysis could be assigned curcumin-modified genes used as biomarkers.[41]
Another study aimed to investigate the short-term effects of supplementation with a Curcumin C3 Complex® on biomarkers of head-and-neck squamous cell carcinoma (HNSCC). The study was an open-label, exploratory biomarker trial of Curcumin C3 Complex® in patients with newly diagnosed HNSCC. Levels of curcumin and its metabolites in tumor and adjacent tissue were determined in patients. Transmucosal administration of microgranular curcumin was well tolerated resulted in improved bioavailability compared to trials that used capsular formulation. It was concluded that curcumin might be beneficial in the preventing of cancer in smokers and tobacco users who are at risk of oral cancer.[42]
To date, limited clinical data exist on curcumin's safety and efficacy in brain tumor patients. A surgical study to evaluate the bioavailability of curcumin in brain tumor patients has been completed, but results have not yet been published.[43]
A Phase II study of curcumin versus placebo for chemotherapy-treated breast cancer patients undergoing radiotherapy has been completed at Emory University (Atlanta, GA, USA). The study was conducted to determine the activity of nuclear factor-κB following curcumin intervention. Meriva® (Curcumin Phytosome® containing curcumin and soy lecithin in 1:2 ratio), a proprietary lecithin delivery system of curcumin, has been evaluated cancer efficacy. Meriva® (500 mg twice daily) was given to the experimental arm. No final results have yet been released.[44]
The clinical trials to assess turmeric and curcumin's efficacy in relieving the side effects of cancer chemotherapy and radiotherapy
A study was conducted to assess whether an individual-specific diet containing turmeric powder had a positive effect on critical clinical measures, such as immune cell-mediated cytotoxicity, serum albumin, derivatives of reactive oxygen metabolites, D-dimer, and fibrinogen. Cancer patients were given chemotherapy treatment support diet or remission support diet for 21–61 days. Both diets contained high plant protein, low glycemic index, and fat. Furthermore, diet and/or turmeric powder was regularly given along with meals. It was concluded that individualized diets with turmeric powder had a beneficial effect on antioxidant status and/or anticoagulant activity in cancer patients receiving chemotherapy and in remission.[45]
The efficacy of turmeric in the prevention of mucositis caused by radiation was evaluated in a single-blind, randomized, controlled clinical trial with head-and-neck cancer patients requiring radiotherapy (70-Gy radiation) or chemoradiotherapy (carboplatin + 70-Gy radiation). Eighty patients were divided into two groups. One group used turmeric mouthwash (400 mg of turmeric in 80 mL of water) (n = 40) whereas the other group utilized povidone-iodine mouthwash (n = 40) during chemo/radiotherapy. Oral mucositis was evaluated using the Radiation Therapy Oncology Group grading system during pretreatment, throughout the study, and posttreatment. This study showed that the group using turmeric as a mouthwash had delayed and decreased levels of radiation-induced oral mucositis compared with the group using povidone-iodine gargle. Moreover, for the group, using turmeric mouthwash had decreased mucositis and showed beneficial effects by delaying and decreasing the intensity of mucositis. Since turmeric can be found easily and not expensive, it may be useful in cancer therapy because of these properties.[46]
Oral mucositis is probably the most common, debilitating complication of cancer patients receiving chemotherapy and radiotherapy. Mucositis restricts the patient's ability to withstand chemo- or radiotherapy and creates difficulties for nutrition. A study was carried out to evaluate the effect of turmeric powder with honey as a complementary therapy for treatment-induced oral mucositis. Sixty cancer patients were divided into two groups: one group had treatment-induced oral mucositis (n = 30) and the second was the control (n = 30) group. It is concluded that application with honey has a beneficial effect on treatment-induced oral mucositis.[47]
Meriva® has been evaluated for its efficacy in relieving the side effects of cancer chemo- and radiotherapy. A semi-quantitative assessment of the side effects was performed using the Visual Analog Scale. Plasma free-radical status was also evaluated in 160 patients. According to the results, lecithinized curcumin may suppress chemo- and radiotherapy-related side effects. The beneficial effects of curcumin can be observed in the upregulation of antioxidant responses and downregulation of inflammatory pathways in tempering the extended and systemic oxidative and inflammatory effects of cancer therapy.[48]
Curcumin has an antioxidant property with both radiosensitizing and radioprotective qualities. A clinical trial was designed to assess the effect of the curcumin-containing product on the oxidative status of prostate cancer patients receiving radiotherapy. Prostate cancer patients were randomly divided into two groups: the first group was treated with radiotherapy and curcumin (CG, n = 20), and the second group was the PG (PG, n = 20). The patients received curcumin (3 g daily) or placebo during external-beam radiation therapy of up to 74 Gy. Serum PSA levels and magnetic resonance imaging/magnetic resonance spectroscopy images were examined. In the CG group, plasma total antioxidant capacity was significantly increased, and the activity of superoxide dismutase was decreased after radiotherapy. PSA levels were decreased in both the groups 3 months after treatment, but no significant differences were obtained between the two groups.[49]
A randomized pilot Phase II trial evaluated the efficacy of a prophylactic topical agent containing curcumin in reducing radiation-induced dermatitis in patients with noninflammatory breast cancer or breast cancer in situ. The curcumin-based gel has been found to decrease the intensity of radiation-induced dermatitis via decreasing water loss and inflammation during radiation therapy. The gel was applied topically to patients who started on the 1st day of radiation therapy and continued 1 week after the completion of radiation therapy.[50]
In another study, the efficacy of a cream containing turmeric and sandalwood oil (Vicco® turmeric cream [VTC], Vicco Laboratories, Parel, India) on radiodermatitis occurring in patients with head-and-neck cancer undergoing radiotherapy was investigated. Fifty patients requiring >60-Gy curative radio-/chemo-radiotherapy were selected. The patients were randomly divided into two groups (25 patients/group). One group received topical application of Johnson's® baby oil, and another group received VTC treatment. Both substances were applied symmetrically in the irradiated area five times a day, and acute skin reactions were evaluated twice a week using Radiation Therapy Oncology Group scores. The study results showed that the VTC of turmeric and sandal oil-based cream effectively prevented radiation-induced dermatitis.[51] However, the results should be confirmed in larger double-blind trials.
A Phase II study to assess curcumin's ability to decrease radiation dermatitis was carried out in a randomized, double-blind, placebo-controlled clinical trial. The study was conducted with 35 breast cancer patients who had severe radiation-induced dermatitis. The patients were adult females with noninflammatory breast cancer or carcinoma in situ prescribed radiotherapy without concurrent chemotherapy. Curcumin C3 Complex as 2 g of curcumin was orally given to patients three times per day during radiotherapy to randomized patients. No significant differences were observed between randomized and PGs for demographics, compliance, radiation skin dose, redness, pain, or symptoms. As a result, 6-g curcumin per day during radiotherapy reduced the severity of radiation-induced dermatitis in breast cancer patients.[5253]
Another study evaluated the effect of curcumin mouthwash on oral mucositis in young adult oncology patients receiving doxorubicin chemotherapy. In addition to standard preventive oral care (0.2% chlorhexidine chloride twice a day for 30 s), the participants used ten drops of Curcumall® (curcumin C3/turmeric liquid extract) twice daily in the mouthwash during chemotherapy treatment. Oral mucositis was evaluated on days 0, 7, 10, 14, and 21. The World Health Organization (WHO) Scale, Oral Mucositis Assessment Scale (OMAS), and Visual Analog Pain ScaleVisual Analog pain scale (VAS; patient reporting scale of 0-10) were used. WHO, OMAS, and VAS scores were lower than the oral mucositis density in four patients compensated for compliance criteria. Four of the five participants developed oral mucositis, but the values were low.[54]
CONCLUSIONS AND FUTURE PERSPECTIVES
Turmeric (C. longa) is called a golden spice that contains curcumin, a bioactive natural compound. Curcumin has numerous pharmacological and therapeutic effects, for which it is called “curecumin.” During the last decade, various clinical trials with curcumin have been completed. In this review, we have analyzed the results of clinical trials conducted in the last 10 years to investigate the importance of curcumin or turmeric alone or in combination with cancer chemotherapeutic agents in different types of cancers and diseases/complications caused by cancer treatment. We have presented 21 clinical trials that have been conducted during the past 10 years. In the view of the above clinical studies, 16 of the 21 clinical trials were associated with the effectiveness of curcumin on various types of cancer, and the other five clinical trials were related to the evaluation of the curcumin's efficacy in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from clinical trials confirm that curcumin has considerable potential to treat cancer patients. However, it is not yet clear whether the long-term use of curcumin supplementation will show similar benefits. It is observed that the probability of using curcumin in the clinics would increase day by day, and in the future, more clinical trials are expected. Furthermore, curcumin's pharmacological properties support its potential to be a drug molecule [Figure 3]. Future investigations should aim to compare different dosages and/or formulations of curcumin, in terms of efficacy and bioavailability. In addition, we should confirm whether curcumin has a synergistic effect when combined with other chemotherapy drugs. It is expected that findings from ongoing and future clinical trials may help the clinical application of curcumin in managing different types of cancer.
Figure 3: Anticancer potential of turmeric bioactive constituent curcumin
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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