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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 175-181

Research on curcumin: A meta-analysis of potentially malignant disorders


1 Department of Oral Medicine and Radiology, Al-Badar Rural Dental College and Hospital, Davangere, Karnataka, India
2 Department of Periodontology, HKES SN Institute of Dental Sciences and Research Center, Davangere, Karnataka, India
3 Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere, Karnataka, India
4 Department of Pharmaceutics, HKES College of Pharmacy, Gulbarga, Karnataka, India

Date of Web Publication13-Apr-2016

Correspondence Address:
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
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.171370

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 > 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.

Keywords: Curcumin, leukoplakia, lichen planus, oral submucous fibrosis, potentially malignant disorders


How to cite this article:
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

How to cite this URL:
Ara SA, Mudda JA, Lingappa A, Rao P. Research on curcumin: A meta-analysis of potentially malignant disorders. J Can Res Ther [serial online] 2016 [cited 2019 Dec 15];12:175-81. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/175/171370


 > Introduction Top


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 OH. 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 Cu 2+ 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 explore and update its interventions used for the management of potentially malignant disorders (PMDs).[1]

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.



 > Materials and Methods Top


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.


Participants included individuals in any age group with a confirmed diagnosis, by clinical examination and or biopsy.

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.

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 Top


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.



Baseline demographic information, such as age and gender, patterns of areca nut and tobacco, was reported in 1 (14%) of 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. [Table 3],[Table 4],[Table 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.
Table 1: Curcumin formulations in clinical trials[2‑5]

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Table 2: Curcumin trials in observational studies[6]

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Table 3: Summary of randomized controlled studies[2]

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Table 4: Summary of randomized controlled studies[3]

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Table 5: Summary of randomized controlled studies[4]

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Table 6: OSMF and curcumin observational studies[7]

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Table 7: Analysis of published data[2‑5]

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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 review, and focusing on mining the studies for information to help direct future research, we developed a list of objectives adapted from (Brown et al., 2006), and summarized in [Table 8].
Table 8: Recommendations for future studies[8]

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  • What populations should be researched?
  • What types of interventions are needed?
  • What types of outcomes should be measured?
  • What study designs are needed?
  • What infrastructure is required to conduct studies?


Population

Subpopulation of patients grouped by disease severity/stage should be studied separately because different interventions may be effective at a different stage of the disease. Studies must define specific inclusion and exclusion criteria to foster the enrollment of subjects suited to the type of intervention. Studies are needed not only in adult population but also in children who are regularly using areca nut products (particularly gutkha) (Gupta and Ray, 2003).[8]

Interventions needed

Habit cessation alone as an intervention may have a large effect, more so on the symptoms of OSMF rather than reversing fibrosis. Complete lack of studies incorporating successful quitting rates suggests that investigators have difficulty managing the dependence on areca nut products. Indeed, the introduction of gutkha into the marketplace in India has led to even higher rates of dependence and OSMF.

  • Habit cessation
  • Future interventions must incorporate a standardized preventive plan if a high rate of relapse is anticipated and include a methodology to allow investigators to control for relapse during the study and follow-up during data analysis
  • Measures of serum/salivary areca alkaloids to check for relapse and continued use of habits
  • Performing a baseline dental prophylaxis to remove extrinsic staining and re-evaluate for new staining
  • Research questions (for early and moderate OSMF)
  • Does a combination of medical therapies provide the best outcomes? Which agents can slow down (or even reverse) fibrosis
  • What are the best delivery systems for medical therapies (i.e., topical vs. submucosal injection vs. systemic agents)
  • Research to consider
  • Specific anti-inflammatory agents and molecular targets to stabilize the disease in early stages and to have an impact on the malignant potential of OSMF.[8]


Outcome measures

  • First
  • Consider the perspective of the patient
  • Morbidity
  • The morbidity associated with OSMF is related to pain/burning, intolerance to spicy foods, beverages as the fibrosis progresses it is related to inability to function, such as opening wide enough to masticate, speak, and in some cases swallow
  • There is the absence of qualitative research on QOL measures in this patient population, and there is a need to develop and validate such instruments until then validated pain scales and pain intensity scales can be used.[8]


Interincisal opening

  • It is the single most reproducible objective measure
  • Ideally, measurements should be made by investigators blinded to the intervention and with intra- and inter-rater reliability assessments.[8]


Degree of tissue blanching, extent of cheek flexibility

  • Difficult to measure
  • Development of new objective measures may have a role and could potentially include sensors to assess tightness of banding or vascular changes.[8]


Laboratory investigations

  • Many patients present with anemias and nutritional deficiencies (Gupta and Maher) so secondary objective measure should be made particularly if designing a medical intervention involves the use of micronutrients, vitamins, or nutritional supplements.[8]


If oral submucous fibrosis + overlapping lesions are present at baseline

  • Protocols for standardized examinations to detect potentially malignant oral diseases, followed by a diagnostic algorithm leading to histopathological diagnosis are of paramount importance (Warnakulasuriya).[8]


Dependence of habits

  • Legislation and education by appropriately targeted health campaigns and mass media communication will reduce its overall use in the community and associated morbidity
  • Potential approaches for cohort studies may include individual, family and group interventions based upon, relapse prevention, and aspects of motivational enhancement therapy (e.g., in combination with potential substitute therapies and flavored chewing gums) or cognitive behavioral therapy.[8]


Study design

Research question should always be framed. Depending on budget and infrastructure habit cessation range from a brief intervention repeated at all visits to intensive counseling (and/or pharmacotherapy). Randomized, double-blinded, placebo-controlled study design is ideally suited to explore the efficacy of medical agents, particularly studies testing agents taken orally where it is feasible to manufacture placebos. Other acceptable designs could be comparison RCTs in which two or more different agents are compared. In such cases, power calculations are important to generate conservative sample sizes depending on expected outcomes to account for differences between active group and controls.[8]

Defining the population should depend on the agent being investigated, such as excluding advanced cases, including those patients with a range of restricted opening, or those with a certain threshold of pain. Preparation of the research infrastructure with Institutional Review Board approval should include a study protocol, consent forms, data entry forms, a budget, and hiring of personnel with training in human subjects research. Randomization, by various acceptable techniques, may be simple or stratified for various severity groups (i.e., early/mild vs. moderate/intermediate OSMF) or other variables such as the presence of dysplasia. All investigators performing procedures (measuring outcomes) must be also be blinded to the treatment arms. In studies with multiple visits, a bonus for completing the trial may help reduce the dropouts. Studies with long-term follow-up are critical to assess relapse and the development of potentially malignant or malignant oral lesions. Loss to follow-up is a major issue, and creative approaches are needed. Future studies should include questionnaires designed specifically to evaluate how well-those treated for OSMF can perform common functions. Study questionnaires could be devised from existing QOL questionnaires, such as the EORTC QLQ-H and N35 (Bjordal et al., 2000), International Classification of Functioning, Disability and Health questionnaire, for patients with head and neck cancer (Tschiesner et al., 2010). Performance status scale (List et al., 1996).[8]


 > Conclusion Top


Only 16 clinical trials on curcumin are currently listed in the national cancer institute website, 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.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 2011;12:332-47.  Back to cited text no. 1
    
2.
Rai B, Kaur J, Jacobs R, Singh J. Possible action mechanism for curcumin in pre-cancerous lesions based on serum and salivary markers of oxidative stress. J Oral Sci 2010;52:251-6.  Back to cited text no. 2
    
3.
Das AD, Balan A, Sreelatha KT. Comparative study of the efficacy of curcumin and turmeric oil as chemopreventive agents in oral submucous fibrosis: A clinical and histopathological evaluation. J Indian Acad Oral Med Radiol 2010;22:88-92.  Back to cited text no. 3
  Medknow Journal  
4.
Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001;21:2895-900.  Back to cited text no. 4
    
5.
Rao KP, Vijaybhaskar D, Pratima S. Formulation of topical oral gel for the treatment of oral sub mucous fibrosis. Sch Res Libr Pharm Lett 2011;3:103-12.  Back to cited text no. 5
    
6.
Deng YT, Chen HM, Cheng SJ, Chiang CP, Kuo MY. Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts: Modulation by curcumin. Oral Oncol 2009;45:e99-105.  Back to cited text no. 6
    
7.
Zhang SS, Gong ZJ, Li WH, Wang X, Ling TY. Antifibrotic effect of curcumin in TGF-ß 1-induced myofibroblasts from human oral mucosa. Asian Pac J Cancer Prev 2012;13:289-94.  Back to cited text no. 7
    
8.
Kerr AR, Warnakulasuriya S, Mighell AJ, Dietrich T, Nasser M, Rimal J, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities. Oral Dis 2011;17 Suppl 1:42-57.  Back to cited text no. 8
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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