ISSN 0973-1482
Journal of Cancer Research and Therapeutics
January-March 2016
Volume 12
Issue 1
• Volume 12 • Issue 1 • January-March 2016 • Pages 1-**** Impact Factor® for 2014 0.791
Official Journal of Association of Radiation Oncologist of India
Original Article
Research on curcumin: A meta‑analysis of potentially malignant disorders ABSTRACT Introduction: Turmeric has been described in ayurveda, and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Various preclinical, clinical, and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic, as a mediator of chemoresistance, chemopreventive, and as a therapeutic agent. Thus, curcumin a spice once relegated to the kitchen shelf has moved into the clinic and may prove to be “Curecumin.” Methodology and Objectives: The focus of this publication is to provide research on curcumin with scientific publications on curcumin indexed in PubMed, Google J-Gate including systematic reviews, randomized controlled trials (RCT’s), observational studies, or case series reports for various potentially malignant disorders (PMD’s) with special attention to studies on oral submucous fibrosis. This research will be valuable in terms of identifying opportunities to provide recommendations for future research, in terms of the populations to research, the types of interventions needed, the types of outcomes to be measured, the study designs needed, to initiate a pathway for a low-cost research plan for future clinical trials in this field with an emphasis on conducting studies in regions of the world where PMD’s are prevalent. Conclusion: There is a lacunae for scientific review of curcumin for PMDs specially on OSMF.Appropriate therapeutic interventions are needed for the initial, intermediate, and advanced stages of the disease. High-quality RCTs should be initiated. KEY WORDS: Curcumin, leukoplakia, lichen planus, oral submucous fibrosis, potentially malignant disorders
INTRODUCTION The belief that plant remedies were natural and superior to man‑made synthetics and the reference to certain historical use by different cultures. Curcumin is a naturally occurring phytochemical and an extract of turmeric. Turmeric is comprised of a group of three curcuminoids: Curcumin (diferuloylmethane), demethoxycurcumin, and bisdemethoxycurcumin as well as volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. Curcumin is a lipophilic polyphenol that is nearly insoluble in water but is quite stable in the acidic pH of the stomach. Animal studies have shown curcumin is rapidly metabolized, conjugated in the liver, and excreted in the feces, therefore, having limited systemic bioavailability. Suppression of the inflammatory response by curcumin as discussed in the preclinical studies involves the inhibition of the induction of COX‑1, COX‑2, iNOS, and production of cytokines such as interferon‑γ. Curcumin has also
been shown to scavenge O2 and OHֹ radicals showing curcumin can have both pro‑oxidant or anti‑oxidant effects depending on the doses and the chemical environment (e.g., availability of free Cu2+ ions). Another free radical, NOS also plays an important role as oxidant, inflammatory agent, and immune‑modulator. Extensive in vitro and in vivo data have paved the way for curcumin to become the subject of clinical trials. Evidence of efficacy has been derived from animal models or small clinical trials. There is only finite data supporting the use of curcumin in phase III trials with specific diseases. However, for the vast majority of conditions, additional early‑phase studies are required to justify larger trials determining efficacy. Hence, this systematic review of curcumin was planned to
Syeda Arshiya Ara, Jayashree A. Mudda1, Ashok Lingappa2, Purushottam Rao3 Department of Oral Medicine and Radiology, Al‑Badar Rural Dental College and Hospital, 1 Department of Periodontology, HKES SN Institute of Dental Sciences and Research Center, 3Department of Pharmaceutics, HKES College of Pharmacy, Gulbarga, 2Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere, Karnataka, India For correspondence: Dr. Syeda Arshiya Ara, Department of Oral Medicine and Radiology, Al‑Badar Rural Dental College and Hospital, Sy. No. 12, Opposite Koranti Hanuman Mandir, Near PDA Engineering College, Gulbarga ‑ 585 102, Karnataka, India. E‑mail: drarshiyazaka@ gmail.com Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.171370
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Cite this article as: Ara SA, Mudda JA, Lingappa A, Rao P. Research on curcumin: A meta-analysis of potentially malignant disorders. J Can Res Ther 2016;12:175-81.
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Ara, et al.: Research on curcumin
explore and update its interventions used for the management of potentially malignant disorders (PMDs).[1]
Participants included individuals in any age group with a confirmed diagnosis, by clinical examination and or biopsy.
Objectives • To develop a systematic map of curcumin interventions available for the management of PMDs • To update the evidence on curcumin interventions used for the management of PMDs • To initiate a pathway for the research plans and the development of protocols for future clinical trials in this field with an emphasis on conducting studies in regions of the world where these diseases are prevalent.
Types of interventions included If curcumin was used as an interventional drug, in which form was it used. As topical agents (mucoadhesive gels, pastes), rinse/oils or systemic (tablets/capsules). The following primary outcome measures were taken into consideration for.
MATERIALS AND METHODS Search strategy Based on the recommendations of the oxford center for evidence‑based medicine cochrane, PubMed, and Google J‑Gate open access journals were used for a period of 10 years from 2002 to 2013 and the following key words and Boolean operators were used curcumin and oral submucous fibrosis (OSMF), curcumin and lichen planus, curcumin and leukoplakia, curcumin and premalignant lesions and conditions. Review methodology Titles and abstracts of potentially relevant studies were selected. Afterward, the full texts of these studies were taken and evaluated whether they matched our inclusion criteria. The initial pool of primary studies and review articles were searched for references leading to additional papers missed in the automated search. Articles that were case reports and statements of expert opinion were only included if they offered some possible insight. Search strategy for oral lesions The search strategy for oral lesions included potentially malignant lesions such as lichen planus and leukoplakia, potentially malignant conditions such as OSMF. Inclusion criteria were Interventional studies Randomized controlled trials • Prospective • Control group • Randomization. Other studies • Nonrandomized prospective • Single intervention • Comparative interventions • Observational studies. Case reports • Retrospective • Intervention. 176
Leukoplakia • Subjective change in severity of oral/mucosal burning pain using any recognized validated pain scale • Subjective change in quality of life (QOL) using any questionnaire. Lichen planus Subjective change in severity of oral/mucosal burning pain using any recognized validated pain scale • Subjective change in QOL using any questionnaire • Reduction in the rate of malignant transformation. Oral submucous fibrosis • Subjective change in QOL using any questionnaire • Reduction in the rate of malignant transformation • Improvement in maximal mouth opening. Secondary outcome measures taken into consideration were • Objective or subjective changes • Adverse events • Improvement in hematological/histopathological/ immunological parameters. Data collection and extraction Studies selected were evaluated independently by single reviewer and the data captured, analyzed for, study period, study design, type, number of subjects, randomization, blinding and time of visits, diagnostic criteria baseline disease severity, outcome measure, follow‑up, statistical analyses, and study setting. RESULTS Seven publications met the selection criteria for the systematic research on the treatment of PMD’s with curcumin. Among 7 studies 5 studies were on human subjects and 2 were on animal subjects. Among the 5 studies on human subjects, 3 were interventional randomized controlled trials (RCT’s), and 2 were observational studies. When the search strategy for individual PMD’s was considered the following data was found. PMDs Leukoplakia Lichenplanus OSMF
Review 0 0 0
Interventional study 2 1 6
Case reports 0 0 0
PMDs=Potentially malignant disorders, OSMF=Oral submucous fibrosis
Baseline demographic information, such as age and gender, patterns of areca nut and tobacco, was reported in 1 (14%) of Journal of Cancer Research and Therapeutics - January-March 2016 - Volume 12 - Issue 1
Ara, et al.: Research on curcumin
the study.[2] Baseline assessment of nutritional or dietary habits was reported in none of the studies. Controls were included in all 5 (100%) human studies. Enrolled population had a wide spectrum of lesions (early to advanced), yet stratification of the study group by the size of lesions, OSMF staging/severity rating/degree of dysplasia was defined at baseline in none of the studies. Sample size in these studies were 75 by Rai et al.,[2] of which 25 cases were of leukoplakia, 25 were of lichen planus, and 25 were of OSMF. 48[3] by Das et al. of OSMF and 7[4] by cheng et al. of leukoplakia. Duration of the study by Rai et al.,[2] was for 9 months,[4] by cheng et al. was for 3 months, and in 1 animal study by Rao et al,[5] was for 6 months. Methodology to diagnose the disease was by clinical evaluation which was confirmed by histopathology in all studies 5 (100%) on human subjects. Three randomized control studies used curcumin as a single agent in the form of capsules and mucoadhesive gel[2,4,5] in PMD’s, 1 randomized controlled study,[3] studied the combination of agents in the form of capsules, turmeric oil, and multinal tablets. One observational study[6] used a single agent 10 μM of curcumin in OSMF. Primary outcome measures were pain control and lesion healing for evaluating cure of oral leukoplakia, oral lichen planus, and OSMF in 2 interventional studies. To measure pain, visual analog scale ranging from 0.5 (very mild pain) to 5 (severe pain) was used. For healing, changes in lesion size, including ulcer size from baseline was used while in OSMF, in addition to the above variables, change in mouth opening was considered in a study by Rai et al.,[2] tongue protrusion and histopathological findings were used in the study by Das et al.[3] In terms of subjective measures, oral burning/pain was the most consistently
measured subjective outcome in all studies. Only one study by Rai et al.[2] used saliva and serum for evaluation of malonaldehyde, 8‑hydroxydeoxyguanosine, and Vitamins C and E as a secondary outcome measure. All these studies met the criteria of randomized/nonRCTs and observational studies, and all these were single‑center studies. There were no studies that looked at the effect of habit control alone as the primary endpoint, that is, cessation of habits. Although the level of reliability (e.g., validation of measurements) was not clearly defined. Other objective measures included changes in tongue movement (i.e., ability to protrude), degree of suppleness of the tissues, amount of blanching of the mucosa, presence of ulceration/vesicle formation, and amount of dorsal tongue papillation, although the methodology for measuring these other objective outcomes was poorly defined and of questionable reliability. Other subjective measures included change in taste, oral dryness, and ability to chew, swallow, or speak. None of the studies used validated instruments evaluating QOL of subjects with OSMF and we could not find any such instruments in the published literature. Table 1 highlight the formulations of curcumin used in different clinical trials and observational studies. Table 2 highlight curcumin trial in an observational study. Tables 3‑5 highlight the summary of randomized controlled studies. Table 6 highlight the summary of Observational study. Table 7 highlight the summary of the analysis of published data of randomized controlled studies. Future recommendations Clinical research methodology has evolved rapidly in some parts of the world, yet elsewhere there is neither the experience, nor the necessary infrastructure, to design let alone run RCTs. While the methodological issues in the published literature we reviewed offer weak evidence at best to make recommendations for the management of patients with PMD’s specially OSMF, there is much valuable insight to be gained from the studies we reviewed. Moving away from the perspective of a systematic
Table 1: Curcumin formulations in clinical trials[2‑5] Title
Author/year
Condition
Formulation
Possible action mechanism for curcumin in precancerous lesions based on serum and salivary markers of oxidative stress
Rai et al./2010[2]
Leukoplakia Capsule Lichenplanus OSMF
Dose
Route of administration Orally
1 g curcumin 900 curcumin 80 mg Desmethoxycurcumin, and 20 mg bisdesmethoxycurcumin OSMF Curcumin capsules 500 mg 2 tablets/day (1 g) Orally Control group Turmeric oil 12 drops of oil (600 mg) Topically Multinal tablets 500 mg tablets 2 tablets/day Orally
Comparative study of curcumin and Das et al./2010[3] turmeric oil as chemopreventive agent in OSMF: A clinical and histopathological evaluation Pathological observations on the Rao et al./2011[5] OSMF (Mice) Mucoadhesive gel treatment of oral submucous fibrosis of curcumin gels in animal models Phase I clinical trial of curcumin, a, Cheng et al./2001[4] Leukoplakia Capsules chemopreventive agent in patients with high risk or premalignant lesions
1% curcumin
Orally
500-1000 mg/day
Orally
OSMF=Oral submucous fibrosis
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Table 2: Curcumin trials in observational studies[6] Title
Author/year
Condition
Arecoline stimulated CTGF production in human buccal mucosal fibroblasts: Modulation by curcumin
Deng et al./2009
OSMF
Dose/ formulation 10 μM
Inference These results indicated that curcumin completely inhibited arecoline‑induced CTGF synthesis and the inhibition is dose‑dependent. Curcumin could be a useful agent in controlling OSMF
CTGF=Connective tissue growth factor, OSMF=Oral submucous fibrosis
Table 3: Summary of randomized controlled studies[2] Authors Rai et al. (2010)[2]
Sample size and conditions 25 OSMF, 25 leukoplakia, and 25 lichen planus patients
Primary outcome measures Pain scores and size of lesion in oral leukoplakia, submucous fibrosis and lichen planus in submucous fibrosis, mouth opening
Secondary outcome measures Salivary and serum oxidative markers such as MDA, 8‑OHdG, Vitamins C and E
Statistical analysis Spearman correlation co‑efficient “r” P value
Results Pain scores and size of lesion in oral leukoplakia, submucous fibrosis and lichen planus improved significantly (P
