From Simple Mouth Cavities to Complex Oral Mucosal Disorders—Curcuminoids as a Promising Therapeutic Approach

Abstract

Oral diseases are among the most common encountered health issues worldwide, which are usually associated with anomalies of the oral cavity, jaws, and salivary glands. Despite the availability of numerous treatment modalities for oral disorders, a limited clinical response has been observed because of the inefficacy of the drugs and countless adverse side effects. Therefore, the development of safe, efficacious, and wide-spectrum therapeutics is imperative in the battle against oral diseases. Curcumin, extracted from the golden spice turmeric, is a well-known natural polyphenol that has been extensively studied for its broad pleiotropic attributes and its ability to modulate multiple biological processes. It is well-documented to target pro-inflammatory mediators like NF-κB, ROS, COX-2, IL-1, IL-2, TGF-β, growth factors, apoptotic proteins, receptors, and various kinases. These properties make curcumin a promising nutraceutical in the treatment of many oral diseases like oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis. Numerous in vitro and in vivo studies have shown that curcumin alleviates the symptoms of most of the oral complications, including the inhibition of the progression of oral cancer. In this regard, many clinical trials have been completed, and many are ongoing to investigate the “curcumin effect” in oral maladies. Therefore, the current review delineates the mechanistic framework of curcumin’s propensity in curbing oral diseases and present outcomes of the clinical trials of curcumin-based therapeutics that can provide a breakthrough in the clinical management of these diseases.

From simple dental cavities to complex oral cancers, oral diseases are the most common health problem faced by individuals worldwide.¹⁻⁶ According to the Global Disease Burden 2017, oral ailments afflict almost 3.5 billion people worldwide annually.⁷ The oral cavity is the body’s crucial contributor in maintaining overall health, and detrimental lifestyle factors lead to the development of several oral diseases such as dental caries, periodontal diseases, preoral lesions, oral cancer, fluorosis of teeth, and other oral manifestations.⁸ Despite the progressive nature and high prevalence of these multigenic diseases, no effective clinical treatment modalities exist for many disorders that ensure a complete cure without a relapse. Though most of the oral diseases could be easily prevented, there exists a high incidence rate that could be due to differences in socioeconomic status and low health literacy awareness especially in middle to low-income countries.^1,9−13 Most of the complications involved in oral ailments are mostly infectious yet preventable and are related to the risk factors which can be classified as modifiable and nonmodifiable. The modifiable risk factors include smoking, tobacco chewing, poor oral hygiene, unhealthy diet, hormonal changes in females, medications, and stress; the nonmodifiable factors include diabetes, aging, and heredity.¹⁴ These factors are linked with the variations caused in the oral microenvironment and decreased immunosurveillance that results in the shift of the oral microbiome and an increase in inflammation which can lead to severe complications, if left unchecked.¹⁵ Apart from the accumulation of plaque-causing bacteria (Streptococcus mutans, Fusobacterium, and Actinobacteria), poor oral hygiene can lead to tooth decay which causes severe discomfort, pain, and social isolation.¹⁶ Increased sugar in the diet can shift the microbiome influx which helps the bacterium to degrade sugars into acids that start to dissolve tooth enamel. Tobacco chewing is also implicated in suppressing the immune response to infections, reducing healing capabilities in accidental wounds, and promoting gingivitis and periodontitis in other noncommunicable diseases.^17,18 Moreover, tobacco chewing in conjugation with alcohol or areca nut is a major risk factor for oral cancer.^19,20

Innovations in the pathophysiological understanding of oral biology have augmented the range of treatment regimens for local and advanced diseases leading to individual treatment plans. Still, these therapeutics suffer from limited clinical success because of the monotargeted approach which in turn produce adverse side effects like vomiting, diarrhea, inflammation, tooth staining, and so on.^11,21 Moreover, prolonged treatment can increase the resistance to antibiotics and chemotherapeutics and make patients susceptible to opportunistic infections.²²⁻²⁵ Therefore, the exploration of various alternative natural products and phytochemicals from plants could be a promising alternative for safe, wide spectrum, and efficacious therapeutic intervention for oral diseases.

The idea to use natural compounds to treat various human diseases has existed since time immemorial, and studies over the decades have proved that these compounds show promising effects against various chronic diseases.²⁶⁻⁴⁵ Curcumin, a natural polyphenol derived from the plant Curcuma longa, has gained immense attention in clinics because of its medicinal and wide pharmacological activities.⁴⁶⁻⁵⁰ The principal pigment in turmeric, that is, curcuminoids, consists of curcumin and its derivatives demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). Accumulating evidence over the past several decades has established curcumin’s anti-inflammatory, antimicrobial, antiproliferative, antioxidant, anticancer, antiaging, antiarthritic, antiatherosclerotic, antidepressant, hypoglycemic, wound healing, and chemosensitization properties.⁵¹⁻⁵⁹ Curcumin with its wide pleiotropic nature can target intricate biological processes and diverse inflammatory factors like cytokines, interleukins (ILs), nuclear factor kappa B (NF-κB), reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), C-reactive proteins, transforming growth factor-β (TGF-β), and other enzymes involved in inflammation. Curcumin also potentially inhibits protein kinase C (PKC), epidermal growth factor–receptor tyrosine kinase (EGF-RTKs), and expression of proteins such as c-jun, c-fos, c-myc, NF-κB-inducing kinase (NIK), mitogen-activated protein kinases (MAPKs), extracellular signal-regulating kinase (ERK), phosphoinositide 3-kinase (PI3K), Akt, cyclin-dependent kinases (CDKs), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and inducible nitric oxide synthase (iNOS).⁶⁰⁻⁶⁷ These attributes make curcumin an interesting and promising candidate to combat numerous oral disorders like oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis (Figure 1). Although turmeric comprises extensive diversity of noncurcuminoid phytochemicals such as zingiberene, curcumenol, curcumol, eugenol, turmerin, turmerones, bisacurone, calebin A, etc., still curcuminoids remain the best-researched active constituent among them.^{35,37,68−70} Numerous in vitro and in vivo studies have advocated curcumin to be safe, well-tolerated, and highly efficacious in the treatment and clinical management of oral diseases. Because of these promising features, curcumin has entered clinical trials for various oral diseases and is also promoted as a nutraceutical or supplement with conventional therapeutics across the globe.⁷¹⁻⁷⁴ Despite all these alluring attributes, curcumin has met limited therapeutic response because of its poor bioavailability and unsuitable pharmacodynamics for in vivo systems. When administered orally, 40–85% of the curcumin passes and remains unaffected through the gastrointestinal tract, where the majority of its flavonoids are metabolized in the intestine and liver. Furthermore, it shows lower tissue accumulation and rapid systematic elimination from the system.⁷⁵⁻⁷⁷ Therefore, substantial efforts have been made at the research front to improve curcumin bioavailability in the human system using adjuncts, nanoparticle formulations, conjugating phospholipid complexes, using synthetic analog, and reformulations using plant oils.^51,78,79 It can be acknowledged that curcumin’s biological and medicinal value far overshadows its lower bioavailability.^80,81 Nonetheless, several formulations of curcumin have already been investigated for increasing the pharmacokinetics of curcumin-based therapeutics. Piperine, an alkaloid well-known for inhibiting hepatic and intestinal glucuronidation has been extensively used in combination with curcumin in the prevention of many chronic diseases. It has been shown that concomitant treatment of 20 mg piperine with curcumin can increase its bioavailability 2000% with no adverse effects.⁸² Therefore, numerous clinical trials are ongoing to explore curcumin’s potential against oral diseases, and results from early studies are quite promising (Clinical Trials.gov Identifier: NCT03790605, NCT03877679, NCT04355416). In this review, we present the comprehensive utility of curcumin-based therapeutics in combating oral diseases. We have highlighted the insights gained from current research that are entering the preclinical evaluation and information about clinical developments, which could help shape the future of curcuminoids in oral maladies.

Figure 1.

Role of curcumin in the prevention and treatment of different oral diseases.

Mechanisms of Action

Curcumin is well-documented to modulate multiple signaling pathways and target diverse protein families like transcription factors, growth factors, apoptotic proteins, inflammatory mediators, receptors, and various other kinases^10,63 (Figure 2). Most of the evidence links inflammation as a major causative factor in the initiation of a variety of oral disorders.⁸³⁻⁸⁵ As the oral cavity is a huge reservoir for microbes making it an ecologically rich microenvironment, the intricate cross-talk between the microbes and host defines the overall health of an individual.⁸⁶ The perturbations in the host cellular machinery initiate the production of several cytokines like tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, IL-7, and so on, at the site of inflammation, which, if left unchecked, leads to the development of various oral diseases like oral submucous fibrosis, oral mucositis, periodontitis, and gingivitis.^87,88 In response to the signal transduction by T-cell receptors, NF-κB is also activated, which further modulates the inflammatory lesions.^89,90 Curcumin is known to target NF-κB, signal transducer and activator of transcription 3 (STAT3), cytokines molecules, COX-2, ROS, C-reactive proteins, TGF-β, and so on, making it a promising molecule against these diseases.^10,61,65 Curcumin showed an anticandida effect with improved ulcer healing efficacy in buccal mucosal ulcers induced in hamsters.^91,92 Curcumin’s anti-inflammatory effects were investigated on lipopolysaccharides (LPS)-induced response in gingival fibroblast in vitro. In that study, curcumin abrogated the production of IL-1β and TNF-α and inhibited the osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) and NF-κB activation.⁹³ Another study explored the efficacy of a curcumin-based mucoadhesive formulation on 5-fluorouracil-induced oral mucositis (5-FU-OM) hamster models. The findings suggested curcumin to have a therapeutic response on OM models by increasing wound healing and modulation of angiogenesis and TGF-β1 expression.⁹⁴ Numerous in vivo studies on periodontal rat models has enumerated the immense potential of curcumin in ameliorating the indices of periodontitis by downregulating the expression levels of TNF-α, IL-1β, IL-6, interferon (IFN)-γ, IL-17, IL-23, MMP-9, p38 MAPK, prostaglandin E2 (PGE2), and NF-κB activity.⁹⁵⁻¹⁰¹ Furthermore, curcumin was also shown to decrease alveolar bone resorption and osteoclastogenesis linked with the experimental periodontal disease models.^102,103 These findings corroborate curcumin to be a robust anti-inflammatory molecule by modulating various signaling pathways and cytokines in suppressing the progression of several oral diseases.

Figure 2.

Curcumin modulates multiple signaling pathways and transcription factors involved in the initiation and progression of various oral disorders.

Apart from having antifungal, anti-inflammatory, and antimicrobial attributes, curcumin has also been investigated for its antineoplastic and antiangiogenic effect in oral cancer. Curcumin has shown promising results for the inhibition of oral cancer in experimental models. Curcumin was reported to abrogate Notch-1 levels, which resulted in reduced NF-κB expression, induction of apoptosis, and inhibition of cell growth and invasion in Cal-27 cell lines.¹⁰⁴ Another study demonstrated curcumin to inhibit proliferation in human squamous cancer cell lines (SCC-4) via the modulation of the cell division cycle protein 27 (cdc27), peroxisome proliferator-activated receptor (PPAR)-α, EGFR substrate 15, and H2A histones.¹⁰⁵ The combinatorial approach of curcumin with gefitinib decreased the total viable cell number by inducing apoptosis and autophagy. Furthermore, downregulation of B-cell lymphoma 2 (Bcl-2) and MMP-9 with upregulation of caspase-3, antihuman light chain 3 (LC3), p62/Sequestosome-1 (SQSTM1), autophagy-related 5 (ATG5), and Beclin-1 expression was observed in human oral cancer SAS cell lines. Besides, the treatment resulted in reduced tumor volume and weight in SAS xenograft nude mice models.¹⁰⁶ Curcumin was observed to promote antitumor response by inhibition of programmed death-ligand 1 (PD-L1) and p-STAT3^Y705 in Cal 27 and FaDu cell lines. Also, curcumin was found to attenuate tumor growth and increase antitumor response in the microenvironment by activation of CD8 positive T cells with a concomitant decrease in T_regs and myeloid-derived suppressor cells (MDSCs) in a 4-nitroquinolone-1-oxide (4NQO) in vivo murine model.¹⁰⁷ A combinatorial approach of curcumin with tea decreased the tumor volume and number of visible tumors by 69.8% and 52.4%, respectively, in 7, 12-dimethylbenz (a)anthracene (DMBA)-induced oral carcinogenesis hamster models. Also, curcumin alone was able to significantly reduce the squamous cancer cell incidence and the proliferation index in hyperplasia, dysplasia, and papilloma during the postinitiation stage.¹⁰⁸ Curcumin inhibited the nicotine-derived nitrosamine ketone (NNK)-induced activation of NF-κB and COX-2 expression in smokeless tobacco extract (STE) exposed oral premalignant and cancer cells.¹⁰⁹ Curcumin exhibited strong antimotility and antiproliferation effects against invasive YD-10B oral cancer cells by downregulating ERK/MAP kinases, NF-κB, urokinase-type plasminogen activator (uPA), and MMP-2/9 expression.¹¹⁰ The anticancer activity of curcumin was also explored in 7,12-dimethylbenz(a)anthracene-induced oral cancer rat models. It was concluded that the treated group showed a reduction in NF-κB and COX-2 expression as compared with the control.¹¹¹ SCC-25 cells, when treated with curcumin, showed decreased cellular proliferation, invasion, and expression of epithelial mesenchymal transition (EMT) markers like, Twist, Snail, and E-cadherin with p53-induced suppression. This study suggested curcumin to be an adjunctive regimen in the treatment and prevention of oral cancer metastasis.¹¹² Administration of curcumin activated the autophagic pathways by formation of autophagic vacuoles and autophagosomes and an increase in expression of LC-II markers leading to the induction of apoptosis in YD10B oral cell lines.¹¹³ Another study explored the efficacy of copper supplementation with curcumin on oral squamous cancer cell lines. The treatment induced intracellular ROS production, increased the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibited EMT markers with increased apoptosis in cancer cells.¹¹⁴ These findings suggested that curcumin can be a potent anticancer agent and can help in augmenting the existing therapies. Thus, curcumin-based therapeutics can induce various signaling cascades; target diverse proteins responsible for proliferation, inflammation; induce apoptosis; and inhibit invasion and angiogenesis, making it one of the most promising natural candidates in the therapeutic intervention of various oral diseases.

Effect of Curcumin against Various Oral Diseases

Numerous preclinical studies have dictated the immense potential of curcumin against a wide variety of oral ailments (Table 1). Also, this golden molecule is deemed safe, efficacious, and well-tolerated in preclinical trials. These promising attributes have invited numerous clinical trials that have expanded their investigations against several oral diseases (Table 2). Though more than 120 clinical trials were completed with curcuminoids, systematic Phase III randomized trials are still needed to validate and translate these findings to establish curcumin as a marketable drug.¹¹⁵

Table 1. In Vitro/In Vivo Studies of Curcumin in Oral Disorders^a.

Oral diseases	Combination	In vitro/in vivo	Model	Mechanism	Reference
Gingivitis	indocyanine green	in vitro	HuGu	↓proliferation	(204)
	-	in vitro	HGEPs	↓TNF-α, ↓IL-1β, ↓IL-6, and ↓MMP-9, ↓NF-κB, ↓TIMP	(208)
	-Phenytoin	in vivo	Wistar rats	↓inflammation, ↓Ki67, ↓α-SMA	(218)
	-	in vivo	HGF/HSG	↑apoptosis, ↑ROS	(199)
	-	in vitro	Gingival fibroblast	↓toxicity, ↑wound healing	(207)
	-	in vitro	Gingival fibroblast	↓TGFβ1, ↓thrombin-induced CCN2	(210)
	-	in vitro	Gingival fibroblast	↓TGFβ1, ↓Smad2, ↓proliferation	(200)
	-	in vitro	Gingival fibroblast	↓TGFβ1, ↓JNK, ↓Smad3, ↓Src, ↓α-SMA	(211)
	genistein	in vitro	Gingival fibroblast	↓uPA, ↓EGF, ↓JNK	(206)
	-	in vitro	Gingival fibroblast	↓TGFβ1, ↓NOX4, ↓JNK, ↓Smad3	(209)
	-	in vitro	Gingival fibroblast	↓CTGF/CCN2, ↓JNK	(201)
	-	in vitro	Gingival fibroblast	↓NF-κB, ↓COX-2	(203)
	insulin	in vitro	Gingival fibroblast	↑wound healing, ↓toxicity	(205)
	insulin	in vitro	Gingival fibroblast	↑apoptosis	(202)
Oral cancer	cetuximab	in vitro	CAL 27 (CAR)	↑caspase-3 and -9, ↓EGFR, ↓ERK, ↓JNK, ↓p38	(230)
	gefitinib	in vitro	SAS	↓MMP, ↑caspase-3, ↓Bcl-2, ↑ATG5,↑LC3, ↑p62/SQSTM, ↑ULK1, ↑VPS34	(106)
	gefitinib	in vivo	SAS cell xenograft nude mice	↓tumor weight, ↓tumor volume	(106)
	green tea	in vivo	Syrian hamsters	↑apoptosis, ↓proliferation, ↓angiogenesis	(108)
	paclitaxel	in vitro	CAL-27	↑apoptosis, ↓Bcl-2, ↓Bcl-2/Bax, ↑Bax, ↑caspase-3	(233)
	-	in vivo	Sprague-Dawley rats	↓NFκB, ↓COX-2	(111)
	-	in vitro	93VU147T	↓Bcl-2, ↓cIAP, ↑Bax, ↓c-Jun, ↓JunB, ↓JunD, ↓p50, ↓p65	(234)
	-	in vitro	. . . . . ...	↓NF-κB, ↓COX-2	(109)
	-	in vitro	SCC25	↓MMP-9, ↓MMP-2, ↓Snail, ↓Twist, ↑E-cadherin, ↑p53	(112)
	-	in vitro	YD10B	↑cleaved PARP, ↑caspase-3, ↑ROS	(113)
	-	in vitro	SCC-25	G2/M phase arrest, ↓MMP-9, ↓MMP-2, ↓uPA, ↓uPAR, ↓p-EGFR, ↓p-Akt, ↓p-ERK1/2, ↓p-STAT3	(240)
	-	in vitro	CAL-27	G2/M phase arrest, ↓Notch-1, ↓Hes-1, ↓Hes-5, ↓Hey-1 ↓Bcl-2, ↓cyclin D1, ↓MMP-9, ↓VEGF	(104)
	-	in vitro	YD-10B	↓MMP-2/9, ↓uPA, ↓uPAR, ↓NF-κB, ↓ERK/MAPK	(110)
	-	in vitro	CAL 27 (CAR)	↑cytochrome c, ↑ APAF-1, ↑AIF, ↑Bax	(229)
	metformin	in vivo	4NQO models	↓Notch-1, ↓STAT 3, ↓CD44, ↓CD133	(235)
	-	in vitro	HPV16+ve/-ve	↑apoptosis, ↓proliferation, ↓miR-21	(239)
	gefitinib	in vitro	SAS	↓proliferation, ↑cytochrome c, ↑caspase-3, ↑PARP, ↑p53	(232)
	-	in vivo	4NQO models	↓PCNA, ↓Bcl-2, ↓SOCS1 e -3, ↓STAT3	(231)
Oral candidiasis	-	in vivo	Hamsters	effective, safe	(92)
	-	in vivo	Mice	↓colony counts, effective	(147)
	-	in vivo	BALB/c mice	↓oral fungal burden	(91)
Oral erythroplakia	-	ex vivo	Chicken buccal mucosa	↑mucoadhesion activity	(146)
Oral mucositis	-	in vivo	Syrian hamsters	↓angiogenesis, ↓TGF-β1, ↑ROS	(94)
Periodontitis	-	in vitro	Gingival fibroblasts	↓TNF-α, ↓IL-1β, ↓NF-κB activation, ↓OPG/sRANKL	(93)
	-	in vitro	Periodontal stem cell	↑TIMP-1, ↓MMP-2	(186)
	-	in vivo	Holtzman rats	↓NF-κB activation, ↓IL-6, ↓TNF-α, ↓PGE2-s mRNA expression	(98)
	-	ex vitro	Human gingival tissue	↓MMP-9	(188)
	-	in vivo	Holtzman rats	↓apoptosis, ↓NF-κB activity	(177)
	-	in vivo	Wistar rats	↓RANKL, ↓RANK, ↓OPG, ↓TNF-α, ↓IL-6	(217)
	-	in vivo	Holtzman rats	↓inflammation, ↓osteoclast counts	(103)
	resveratrol	in vivo	Wistar rats	↓TNF-α, ↓IFN-γ, ↓IL-1β	(96)
	-	in vivo	Sprague-Dawley rats	↓inflammation, ↓MMP-9, ↓TNF-α, ↓IL-1β, ↓IL-6	(180)
	piperine	in vivo	Holtzman rats	↓NF-κB activity, ↑TGF-β1	(97)
	-	in vivo	Holtzman rats	↓MMP-9, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓NF-κB activation, ↓p38 MAPK	(179)
	-	in vivo	Wistar rats	↓IL-17, ↓RORγt, ↓IL-23, ↓IL-1β, ↓IL-6	(176)
	-	in vivo	Holtzman rats	↓TNF-α, ↓osteoclastogenesis	(102)
	-	in vivo	Wistar rats	↓IL-1β, ↓IL-10, ↓alveolar bone loss	(95)
	-	in vivo	Holtzman rats	↓NF-κB activity, ↓p38 MAPK, ↓ PGE2 synthase, ↓IL-6	(182)
	insulin	in vivo	Wistar rats	↓TNF-α, ↓IL-1β, ↓IL-6, ↓IFN-γ, ↓IL-17	(99)
	-	in vivo	Sprague-Dawley rats	↓MMP-9, ↓TNF-α, ↓IL-1β	(100)
	-	in vivo	Wistar rats	↓IL-1β, ↓IL-6, ↓IL-17, ↓IL-23	(101)
	-	in vivo	Wistar albino rats	↓edema, ↓inflammation	(183)
	-	in vivo	Holtzman rats	↓MMP-8, ↓IL-6, ↓IL-1β	(181)
	-	in vivo	Dogs	↓MMP-9, ↓IL-1β, ↓IL-6, ↓p38 MAPK	(178)

^aAbbreviations: AIF: apoptosis inducing factor, APAF1: apoptotic protease activating factor 1, ATG5: autophagy related 5, Bax: B-cell lymphoma 2-associated X protein, Bcl-xL: B-cell lymphoma-extra-large, Bcl-2: B-cell lymphoma 2, CCN2: cellular communication network factor 2, cIAP: cellular inhibitor of apoptosis protein, COX-2: cyclooxygenase-2, CTGF: connective tissue growth factor, EGFR: epidermal growth factor receptor, ERK: extracellular signal regulating kinase, Hes: hairy/enhancer of split, Hey-1: Hes related with YRPW motif protein 1, HGEPs: human gingival epithelium progenitors, IFN: interferon, IL: interleukin, JNK: Jun N-terminal kinase, LC3: antihuman light chain 3, MAPK: mitogen-activated protein kinase, MMP: matrix metalloproteinase, NF-κB: nuclear factor kappa B, NOX: NADPH oxidase; OPG: osteoprotegerin, PARP: poly (ADP-ribose) polymerase, PCNA: proliferating cell nuclear antigen, PGE2-s: prostaglandin E2 synthase, RANK: receptor activator of nuclear factor kappa-B, RANKL: receptor activator of nuclear factor kappa-B ligand, RORγt: retinoic-acid-receptor-related orphan nuclear receptor gamma, ROS: reactive oxygen species, SMA:smooth muscle actin, SOCS: suppressor of cytokine signaling, STAT3: signal transducer and activator of transcription 3, SQSTM1: sequestosome-1, TGF-β1: transforming growth factor-β1, TIMP: tissue inhibitor of metalloproteinases, TNF-α: tumor necrosis factor-α, uPA: urokinase-type plasminogen activator, ULK: Unc-51 like autophagy activating kinase, uPA: urokinase-type plasminogen activator, uPAR: urokinase-type plasminogen activator receptor, VEGF: vascular endothelial growth factor, VPS 34: vacuolar protein sorting 34, 4-NQO: 4-nitroquinolone-1-oxide.

Table 2. Clinical Trials of Curcumin/Curcuminoids/Turmeric Used in Different Oral Diseases.

Oral diseases	Combination	Phase	Patients	Outcome	Reference
Aphthous stomatitis	-	-	60	effective	(151)
	-	-	16	effective	(153)
	-	-	40	effective	(155)
	-	-	105	effective	(156)
	-	-	58	effective	(154)
	-	-	57	effective; ↓pain, ↓ulcer size	(152)
Gingivitis	-	-	30	effective	(214)
	-	-	60	effective	(198)
	-	-	30	effective	(213)
	-	-	150	effective	(215)
	-	-	40	effective	(220)
	lycopene and piperine	-	60	effective	(219)
Oral erythroplakia	-	-	10	effective; ↓pain, ↑healing	(146)
Oral leukoplakia	-	II B	223	well-tolerated	(143)
Oral mucositis	-	-	20	effective	(129)
	-	-	32	effective	(131)
	-	-	40	safe and effective	(136)
	honey	-	60	effective	(138)
	-	-	7	safe and well-tolerated	(137)
Oral submucous fibrosis	-	-	48	beneficial and effective	(125)
	-	-	40	beneficial and effective	(124)
	-	-	30	effective	(128)
		-	30	effective	(116)
	tulsi	-	41	safe and effective	(123)
	-	-	30	significant improvement	(121)
	-	-	28	efficient	(126)
	-	-	60	effective	(127)
	-	-	90	significant improvement	(118)
	-	-	119	effective	(73)
	lycopene and piperine	-	40	significant improvement	(122)
	triamcinolone-hyaluronidase gel	-	120	significant improvement	(71)
Oral lichen planus	-	-	40	effective	(163)
	-	-	50	complete remission	(168)
	-	-	20	no detectable effects	(161)
	-	-	75	improvement	(164)
	-	II	20	well-tolerated	(162)
	-	-	27	effective	(166)
Periodontitis	-	-	30	effective	(191)
	-	-	20	significant improvement	(193)
	-	-	23	beneficial and effective	(195)
	-	-	30	significant improvement	(216)
	photodynamic therapy	-	25	short-term clinical benefits	(190)
	-	-	10	significant improvement	(192)
	-	-	30	mild/moderate improvement	(189)
	-	-	30	significant improvement	(184)
	-	-	20	Effective	(187)
	-	-	30	significant improvement	(185)
	-	-	23	mild improvement	(195)

Oral Submucous Fibrosis (OSMF)

Oral submucous fibrosis (OSMF) is a chronic, fibrotic disorder of the mouth, oropharynx, and upper part of the esophagus that advances with time and is generally associated with major functional morbidity and an increased risk in malignancy.^116−118 It generally afflicts the oral mucosa of males in the age group of the 20s to 40s.¹¹⁹ Most of the cases of OSMF are exorbitant in South Asian populations majorly because of their habit of areca nut chewing. Different kinds of treatment regimens are available which focus on palliative care and not the complete cure. Curcumin is a well-known anti-inflammatory mediator and is known to improve the symptoms of OSMF significantly. Various clinical investigations are ongoing to explore the curcumin potential as a drug or adjunct in the treatment of OSMF patients.^71,120−124

A study was carried out to investigate the effectiveness of curcumin dispensed in two forms, mainly curcumin capsules and turmeric oil in 48 OSMF patients. Patients were clinically and histopathologically evaluated for OSMF and were classified into three groups: Group I was administered with curcumin capsules; Group II with turmeric oil; and Group III as control were delivered muttinal tablets for 3 months and 6 months follow up. The combinatorial group (curcumin and turmeric oil) resulted in the improvement of clinical signs and symptoms and also showed histopathological reversal as compared with other control groups.¹²⁵ Another study compared the efficacy of curcumin with the existing Tenovate ointment for 30 OSMF patients. Two different cohorts containing 15 patients in each group of control and treated were topically administrated Tenovate ointment (clobetasol propionate (0.05%) and Longvida (curcumin) lozenges on control and treated group respectively for 3 months duration and 6 months follow-up study. Treatment of curcumin resulted in the overall improvement of mouth opening and visual analogue scale (VAS) for regular food and VAS for spicy food status.¹¹⁶ A pilot study investigated the expression level of different proteins such as p53, TGF-β, and iNOS in 28 OSMF patients during pre and postcurcumin administration. These proteins are known mediators of OSMF pathophysiology and inhibiting them might be a novel approach for the clinical management of OSMF. It was observed that curcumin intake could downregulate the expression of proteins which suggested curcumin’s chemopreventive attribute in the management of OSF.¹²⁶ Another study assessed the potential of curcumin and lycopene in patients suffering from OSMF. The study group consisted of 60 patients who were equally divided into Group A and B and were administrated with lycopene (4 mg) and curcumin (300 mg), respectively, thrice a day for 3 months. Both the groups showed a decrease in burning sensation in OSMF patients; however, contrastingly, lycopene was more effective for improvement in mouth opening.¹²⁷

In a recent study, curcumin administration led to a significant overall improvement in the symptoms of OSMF, such as mouth opening, burning sensation, tongue protrusion, and cheek flexibility.¹¹⁸ Similarly, six other clinical trials explored curcumin’s potency to curb OSMF in 298 patients. Three studies showed marked amelioration in burning sensation as compared with the other control patients.¹¹⁹ A similar improvement in burning sensation was observed with commercial turmeric treatment in 30 patients.¹²⁸ In another study, 119 patients were categorized into three groups, where the patients in group I received antioxidants, group II received systemic curcumin, and group III received both systemic and topical curcumin. All the groups showed improvement in the symptoms such as opening of the mouth, burning sensation, and tongue protrusion after the 12th week; however, group III patients showed substantial improvements as compared with the other two groups corroborating the necessity of a combinatorial approach for curbing OSMF.⁷³ These findings suggested curcumin to be safe and efficacious in improving the deleterious symptoms of OSMF patients.

Oral Mucositis (OM)

Oral mucositis (OM) is a complex and unique pathological condition that arises because of mucosal injuries which are generally outcomes of the patient’s treatment regimens under conventional chemotherapy and radiation therapy.¹²⁹ The symptoms usually represent erythema and burning sensation and may evolve to noticeable painful ulcerative lesions affecting the patient’s ability to eat and speak, thus affecting overall health.¹³⁰ Curcumin, being an anti-inflammatory molecule, could play a vital role in palliative care and management of this disorder.¹³¹

In the oral mucositis in vitro model, naturally purified curcumin was compared with synthetic curcumin to find the bioequivalence of both formulations. It was observed that both forms of curcumin are equally effective in inhibiting pro-inflammatory cytokines such as IL-8 and IL-6.¹³² A study presented the antifibrotic potential of curcumin through the inhibition of proliferation in fibroblasts and myofibroblasts from the human oral mucosa, downregulation of type I and III collagen in myofibroblasts, and deregulation of the cell cycle. It was also found to induce apoptosis in the myofibroblasts cells through the downregulation of the B-cell lymphoma 2(Bcl-2)/B-cell lymphoma 2-associated X protein (Bax) ratio.¹³³ Interestingly, an in vivo study investigated the effects of curcumin and capsaicin with or without visible light irradiation on the oral mucous membrane. Both the compounds were observed to induce apoptosis and could act as photosensitizers when exposed to visible light in the presence of oxygen; therefore, these compounds could be used as photodynamic therapy in this oral ailment.¹³⁴ Another in vivo study on 72 hamsters determined the effect of a mucoadhesive formulation containing curcuminoid (MFC) from C. longa extract on 5-FU-OM models divided into four groups (i.e., control, placebo, chamomilla, and MFC). Clinical and histopathological investigations revealed that MFC and chamomilla groups exhibited better efficiency of wound healing. Furthermore, MFC cohorts showed reduced angiogenesis and TGF-β1 expression, suggesting the therapeutic potential of MFC in curbing OM.⁹⁴ These preclinical studies advocated the use of curcuminoids either as drug or adjunct in treatment and prevention of oral mucositis.

A nontoxic formulation containing curcumin, α-tocopherol, and sunflower oil resulted in reduced occurrence of radiation-induced mucositis, which validated the effectiveness of the combinations against the disease.¹³⁵ Curcumin gel, when topically administered, was found to be safe, effective, and a promising alternative in treating oral mucositis.¹³⁶ A pilot study was conducted to determine the tolerance of curcumin mouthwash with pediatric OM patients undergoing current doxorubicin-comprising chemotherapy. The curcumin containing mouthwash was found to be safe and well-tolerated in OM patients.¹³⁷ Another study evaluated the effectiveness and safety profile of curcumin in combating OM. Twenty cancer patients undergoing radio-chemotherapy were segregated into two groups, in which group I was administered with regular chlorhexidine mouthwash 0.2% and group II with fresh curcumin mouthwash thrice a day. The follow-up was monitored at day 0, 10, and 20, in which curcumin administration was found to be more effective in terms of NRS (numerical rating scale), erythema, ulceration, and WHO scores. It further showed better wound healing and patient compliance in managing radio-chemotherapy-induced OM.¹²⁹ Another study investigated the effect of turmeric powder in combination with honey on 60 OM patients. Patients were selected on the basis of the nonprobability purposive sampling method and were divided into an experimental and control group with 30 patients each. It was found that the applied turmeric with honey was effective in improving the symptoms of patients with OM conditions.¹³⁸ These findings indicated curcumin to be efficacious in reducing the chemo/radiotherapy-induced inflammations in patients, and their association can be an indicator of improved quality of life in OM patients

Oral Leukoplakia

Oral leukoplakia clinically present as white lesions in the oral mucosa, some of which can lead to malignant transformation.^139,140 It is considered as the most common oral precancerous lesion that can progress to invasive oral cancer ranging from 0% to 36% if left untreated.^141,142 A randomized study was undertaken to investigate the safety and efficacy of curcumin in 223 oral leukoplakia patients, out of which 112 patients were grouped in the placebo and 111 patients were administered curcumin (3.6 g/day) orally for 6 months. The treatment was well-tolerated with a significant and durable clinical response for 6 months in 75 (67.5%) patients.¹⁴³

Oral Erythroplakia

As stated by the WHO in 1978, oral erythroplakia present as bright red color velvety plaques having excluded other red conditions that can be defined clinically or histopathologically. It is also recognized with higher rates of malignant transformation.^144,145 The evaluation of curcumin solid-lipid nanoparticle (CurSLN)-loaded with mucoadhesive gel was tested in in vitro drug dialysis and 10 patients suffering from oral erythroplakia. In the same study, the buccal mucosa of the chicken showed that CurSLN had remarkable muco-adhesion activity, and histological examination showed a major amount of curcumin retained in the chicken oral mucosal tissue when monitored for ex vivo muco-adhesion test and ex vivo permeation study. Furthermore, short-term evaluation of CurSLN efficacy on 10 erythroplakia patients resulted in reduced pain and complete healing after 6 weeks of treatment.¹⁴⁶ Though curcumin has been found to exhibit strong pharmacological activity against oral erythroplakia, very limited clinical trials have investigated its existing potential against these disorders.

Oral Candidiasis

The wide variety of human oral infections, from localized mucocutaneous lesions to serious invasive processes, usually arises due to the invasion of harmful pathogens. Some of these infections with clinical significance include oropharyngeal candidiasis and Candida-related denture stomatitis.¹⁴⁷ Oral candidiasis is one of the common oral infections that are usually caused by an overgrowth of Candida species, most commonly the Candida albicans.^148,149 The oral administration of curcumin with the dosage of 20, 40, and 80 μM in the immunosuppressed mice caused a significant decrease in C. albicans growth after photodynamic therapy in all doses plus LED exposures. However, the highest reduction of log₁₀ in colony counts (4 logs) was observed for the 80 μM dose of curcumin, which indicates that curcumin acted as an effective photosensitizer against C. albicans to inactivate it without destroying the healthy tissue of the host mice.¹⁴⁷ Similar treatment with curcumin at 40 μM in the presence of light imparted a major antifungal effect against the yeast populations of C. albicans, C. glabrata, and C. tropicalis and also decreased the metabolic activity and biofilm biomass of all the species.¹⁵⁰

Aphthous Stomatitis

Aphthous ulcer, also referred to as recurrent aphthous stomatitis (RAS), is one of the most common ailments characterized by the development of painful, recurring solitary or multiple ulcers in the oral cavity.¹⁵¹ Accumulating evidence has implicated the usefulness of curcumin-based therapeutics in various in vitro and in vivo models of RAS. A randomized clinical trial was investigated to assess the safety and efficacy of curcumin in 60 patients diagnosed with RAS. Patients were divided into two treatment groups: Group I and Group II treated with curcumin gel and triamcinolone acetonide gel, respectively, for 3 times/day. The findings reported a significant difference in size, pain, number, and duration of ulcers in both groups within a 7-day period.¹⁵¹ A similar study performed with 28 patients treated with curcumin gel (containing 2% curcumin), and 29 patients in placebo gel treatment for 2 weeks resulted in a reduction of pain intensity and size of the ulcer, which suggested that curcumin is effective against minor aphthous stomatitis.¹⁵² A comparative study involving 16 minor RAS patients with the application of 2% turmeric extract gel reduced the erythematous halo, ulcer size, and pain intensity in patients.¹⁵³ Besides, the treatment with curcumin orabase in 29 patients was reported to be effective in reducing the size of oral lesions, which is similar to the effect of standard control in patients (n = 29) with 0.1% of triamcinolone acetonide treatment.¹⁵⁴ Moreover, in a study comparing the effect of curcumin with the triamcinolone acetonide treatment in 20 patients, it was found that both treatments were equally effective and safe in RAS patients.¹⁵⁵ In a recent study, curcumin treatment yielded significant results in terms of improvement in size, VAS score, erythema, and exudations.¹⁵⁶ These findings suggested curcumin to be efficacious in the treatment and palliative care of recurrent aphthous stomatitis patients.

Oral Lichen Planus (OLP)

Oral lichen planus is a comparatively common disorder, estimated to affect 0.5% to 2.0% of the general population.^157,158 It is due to abnormal T cell immune response where the epithelial cell’s surface antigenicity is recognized as foreign.¹⁵⁸ Lichen planus is a mucocutaneous disease that affects buccal mucosa, gingiva, and tongue, with sites of palate lesions being rare.¹⁵⁹ This disease can be clinically classified into different forms, such as reticular, papular, plaque-like, atrophic, erosive, and bullous.¹⁶⁰ Most of it is nonsymptomatic, where the atrophic erosive can produce symptoms that range from burning sensation to severe pain, causing interference in speaking, eating, and swallowing.¹⁵⁸ Curcumin has been found to be well-tolerated and effective in ameliorating the symptoms of OLP, while in some studies it leads to complete remission.^161−164

In one of the clinical studies, curcumin was found to be safe and well-tolerated when the initial dose started at 1 g for 2 weeks, followed by a reduced dose of 500 mg for the next 2 weeks and then to 250 mg for the next 2 weeks, followed by 1 month of local application. There was significant amelioration in symptoms with no change in normal mucosa appearance, and recurrence was also not observed in the patients after curcumin treatment.¹⁶⁵ Another study explored the efficiency of curcumin in comparison with triamcinolone acetonide for 27 OLP patients. The subjects were divided into two groups: Group I with 12 patients treated with 0.1% triamcinolone acetonide and Group II having 15 patients treated with curcumin ointment, thrice a day for a 2-week period, where it was observed that curcumin cohort improved in relation to pain, erythema, and ulceration. These results indicated that curcumin could be an alternative to steroid treatment of OLP.¹⁶⁶ Curcumin treatment also mediated the increase in vitamins C and E levels that helped in the prevention of lipid peroxidation and DNA damage.¹⁶⁷ In a study comparing the efficacy of triamcinolone and curcumin, 50 OLP patients in the age range of 38–73 years were divided into groups, each of which received either 0.1% triamcinolone or 5% curcumin oral paste thrice a day for 4 weeks. At the end of the study, the complaints of burning sensation, itching, mild swelling, and xerostomia had disappeared during the first week of treatment.¹⁶⁸

Dental Caries

Dental caries may be defined as an infectious microbiological disorder of the teeth that leads to local dissolution and destruction of the calcified tissues. It is the second leading cause of tooth loss globally irrespective of age, sex, caste, creed, or geographic location.¹⁶⁹ The formation of the microbial biofilm leads to an acidic and anaerobic state that results in the progression of dental caries because of adherence and colonization of Streptococcus mutans (S. mutans).¹⁷⁰ Other factors that are responsible for the initiation of this disease include cariogenic bacteria, fermentable carbohydrates, a susceptible tooth, host, and time; however, the risk factors in infants and young children may vary because their bacterial flora and host defense mechanism are in the process of development and the surface of the tooth that are at new eruption might show hypoplastic defects which may require diet negotiation.

Curcumin treatment was reported to exert antibiofilm activity from the 5th minute to the 24th hour, and the sessile minimum inhibitory concentration (SMIC 50%) against the biofilm of S. mutans was reported to be 500 μM. Moreover, curcumin treatment could also abate live bacterial count and decrease short-term production of extracellular polysaccharide and genes related to polysaccharide synthesis, carbohydrate metabolism, adherence, and the two-component transduction system.¹⁷¹ Another study evaluated the effect of curcumin on inhibition of S. mutans’ adherence to collagen and fibronectin-coated glass surfaces and in vitro inoculated human teeth surfaces (related to oral conditions in vivo). It was observed that curcumin inhibited bacterial growth completely at a minimum inhibitory concentration (MIC) of 128 μg/mL, and the concentration below MIC inhibited bacterial adherence to the glass and tooth surfaces, suggesting the antiadhesive activity mediated through collagen and fibronectin. This property also suggested the use of curcumin as a food-based antimicrobial agent.¹⁷² Further, the antibacterial activity of the novel nanocomposite of carboxymethyl starch (CMS)-chitosan (CS)-montmorillonite (MMT) for the delivery of curcumin was investigated against S. mutans, which showed effective inhibition on the biofilm formation on dental models.¹⁷³

Periodontitis

Periodontitis is a disease with chronic inflammation of supporting structures of teeth because of the formation of bacterial biofilm near the tooth surfaces. The pathogenic microbes activate the progression of the disease, yet most damage to periodontium is due to the host’s immune response against the bacterial pathogens.¹⁷⁴ The extent of inflammation or the swelling caused at surgical sites following periodontal therapy might drive one of the particular sensations, such as postoperative pain, which could degrade the quality of life.¹⁷⁵ Curcumin has been demonstrated to decrease the expression of various inflammatory markers and angiogenic factors in different preclinical models of dogs and rats making it a potent candidate for human clinical trials.^{101,176−183} Thus, numerous clinical studies of curcumin (supplement or gel-based form) have been undertaken to tackle and prevent chronic periodontitis.^184−193 The mucoadhesive film of curcumin had shown its analgesic attributes, leading to reduced postoperative pain and swelling over a week after periodontal surgery.¹⁷⁵ Also, the local administration of curcumin-loaded nanoparticles in 16 rats divided into two groups (LPS-injected group and vehicle control group) showed marked inhibition of inflammation and bone resorption that are associated with periodontal symptoms.¹⁰³

In a retroprospective study, with a nonsurgical approach, the effect of curcumin collagen gel was compared with the conventional chlorohexidine (CHX) chips as adjuncts to mitigate scaling and root planning for chronic periodontitis patients. After 6 months, patients were monitored on the basis of pocket depth and clinical attachment levels to access the efficacy of the treatment. The findings reported a significant decrease in gingival and plaque index scores with ameliorated microbial parameters, indicating curcumin’s efficiency in curbing the symptoms for chronic periodontitis patients.¹⁹⁴ Similar investigations have been carried out by other groups where 1% of curcumin irrigation was used as a supplement before scaling and root planning.^195,196 Hence, observations from the earlier studies led to the use of 2% whole turmeric gel, which was reported to have higher pharmacological activity and can be used as a supplement in the treatment and palliative care of periodontal pockets.¹⁹⁷ Treatment indicated relief in inflammatory symptoms with a mild to moderate beneficiary effect for cases of chronic periodontitis. A randomized, double-blinded Phase III clinical trial (ClinicalTrials.gov Identifier: NCT03790605) is ongoing to investigate the administration of 1% curcumin chips locally in a nonsurgical isolated periodontal pocket.

Gingivitis

Gingivitis is a common periodontal disorder that afflicts more than 80% of the population worldwide.¹⁹⁸ It is an inflammation of the gums due to the accumulation of plaque or bacteria. Curcumin-based therapeutics hold great potential in the treatment of gingivitis because of their anti-inflammatory and antioxidant activity. Numerous in vitro studies of curcumin treatment on gingival fibroblasts have shown inhibition of proliferation and angiogenesis with downregulation of several inflammatory markers like TNF-α, TGFβ1, NF-κB, IL-1β, and IL-6.^199−211 In a study, whole turmeric formulation exhibited a similar response as that of curcumin extracts in the prevention and treatment of plaque and gingivitis.²¹² As curcumin posesses anti-inflammatory attributes, its mouth wash formulations were observed to be equally efficacious as CHX and can be used as a potential supplement in mechanical periodontal therapy.²¹³ Similarly, another study compared curcumin’s efficacy with the CHX-metronidazole (MTZ) combination. Administration of curcumin was found to be as effective as CHX-MTZ, and it reduced the CCL28 and IL-1β level better than the combinatorial formulation.¹⁹⁸ Similar studies involving curcumin mouth rinse had been shown to reduce reactive oxygen metabolites (ROM) levels at the end of 4 weeks, which suggest the alternative approach to gingivitis treatment using curcumin-based therapeutics.²¹⁴ Another study exhibited curcumin mouthwash activity against plaque and gingivitis by reducing the plaque index (PI), gingival index (GI), and sulcus bleeding index (SBI) scores.²¹⁵ Further, the curcumin gel application combined with scaling and root planning had ameliorated the periodontal parameters such as PI, GI, probing depth (PD), clinical attachment level (CAL), and microbiologic parameters in test groups as compared with the control (without curcumin gel and only SRP).²¹⁶ Another study evaluated the efficiency of intragastric administration of curcumin where it was observed to reduce the alveolar bone loss through the abridged expression of inflammatory mediators like receptor activator of nuclear factor-κB (RANK), RANKL, and OPG.²¹⁷ Furthermore, curcumin could decrease phenytoin-induced gingival expansion by decreasing the expression of Ki67 and alpha-smooth muscle actin (α-SMA), inflammation, epithelial thickness, and number of blood vessels with an increase in cross-sectional area.²¹⁸ The treatment of curcumin could be effectively used to control the plaque spread which might be due to its anti-inflammatory action in the gingivitis.^219,220

Oral Cancer

Oral squamous cell carcinoma (OSCC) is one of the most frequent malignant tumors of the oral cavity associated with high incidence and mortality rates worldwide.^5,221,222 It has become a major public health problem in Southeast Asia because of the habit of chewing tobacco, smoking, and the use of alcohol.^223−225 The oral squamous cell carcinomas (OSCC) constitute more than 90% of oral cancers that originate from the squamous cell lining of the lip or oral cavity.^226,227 Though any abnormality in the oral cavity is easy to monitor, still most of the OSCC cases are diagnosed at advanced stages, which results in reduced overall and progression-free survival rates.^226,228 Accumulating evidence has implicated the usefulness of curcumin-based therapeutics in various in vitro and in vivo models of oral cancers.^{106,111,229−235}

The dose-dependent curcumin treatment was reported to inhibit PD-L1 and p-STAT3^Y705 expression and also reduced the tumor growth in oral cancer cell lines.¹⁰⁷ Besides, the administration of curcumin downregulated the expression of Notch1, which further lead to reduced expression of NF-κB that cause inhibition of cell growth and invasion.¹⁰⁴ The combinatorial approach of tea and curcumin in DMBA-induced oral cancer hamsters’ models exhibited reduced tumor volume and incidence, which were correlated with decreased cellular proliferation, induction of apoptosis, and inhibition of angiogenesis.¹⁰⁸ Similarly, the combination of curcumin and lycopene administered at different doses of 3, 4.25, 5.50, and 6.75 μM resulted in increased cell cytotoxicity and decreased migration in oral cancer cell lines. Moreover, this combination, along with irradiation, exhibited favorable synergistic activity against oral cancer.²³⁶ Further, curcumin treatment could dose-dependently inhibit cell proliferation and invasion and also influence the cell cycle of the SS4 cells dose-dependently.¹⁰⁵ In another study, curcumin was reported to possess anticancer attributes against OSCC via induction of autophagy and apoptosis through the production of ROS and autophagic vacuoles formation.¹¹³ Curcumin could also increase the expression of CCAAT/enhancer-binding protein alpha (C/EBP α) through the activation of p38 and its interaction to binding elements of insulin-like growth factor binding protein 5 (IGFBP-5) promoter region, which induced the level of IGFBP-5 that further complemented the reduced xenograft tumorigenesis in mice.²³⁷ Further reduction of luciferase activity and base excision repair (BER) expression and PARylation suggest the promising efficiency of curcumin and olaparib in combination to inhibit BER activity in the oral cells. In vivo study of curcumin with olaparib showed a similar outcome with the decreased tumor growth and induction of apoptosis and improvement in body weight of tumor mice.²³⁸

Curcumin treatment in the range of 0–50 μM dose dependently inhibited the cancer cell proliferation, stemness, and expression of miRNA-21 in human papillomavirus (HPV)+ve/HPV-ve oral cancer cells. Furthermore, the effect was more prominent in the case of HPV-positive cancer stem cells (CSCs) as compared with the other cancer cells.²³⁹ Administration of curcumin with copper adjunct enhanced the suppression of proliferation and migration by upregulating the E-cadherin expression with a simultaneous decrease in Vimentin levels in oral cancer cells, which led to the suppression of EMT. Moreover, the combinatorial strategy also induced early apoptosis in the cancer cells as compared with single curcumin or copper treatment.¹¹⁴ Further, treatment of curcumin in 4NQO-induced oral carcinogenesis model for 12 weeks at 100 mg/kg significantly reduced the expression levels of proliferating cell nuclear antigen (PCNA), Bcl-2, suppressor of cytokine signaling (SOCS)-1 e -3, and STAT3 and also eliminated the cellular atypia and minimized genes associated with EMT.²³¹ Though curcumin has shown the potential to inhibit proliferation, migration, and invasion with increased apoptosis, more randomized clinical trials are paramount for establishing curcumin as an alternative approach in the clinical management of oral cancer.

Conclusions

As well-documented, oral diseases afflict millions worldwide and intense research is going on globally to find efficient, specific, and targeted natural compounds that can replace the nonspecific, nontargeted drugs and their associated debilitating side effects. For 200 years, curcumin, the golden nutraceutical has been researched for its wide pleiotropic activities and multitargeted approach against different chronic diseases. The current review mainly highlights the therapeutic potential of curcumin in treating several oral diseases like oral cancer, oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis. The focus of this review is to elucidate the effects of curcumin on the inhibition of various proteins and signaling pathways associated with the development and progression of oral diseases.

Turmeric or Curcuma longa is a perennial herb belonging to the family of Zingiberaceae, which is mostly used in South Asian countries for decades as a spice, food preservative, and coloring agent. Although turmeric has more than 300 active compounds, curcumin has been extensively studied and researched with over 16 000 citations in PubMed. Curcumin has been well-documented to induce anti-inflammatory, antiangiogenic, antioxidant, anticancer, antimicrobial, and wound healing attributes against various diseases including oral disorders. These traits make curcumin a promising nutraceutical in the treatment and palliative care of several oral pathological diseases such as oral mucositis, oral cancer, gingivitis, oral lichen planus, etc. Curcumin has been reported to ameliorate the overall status of oral mucositis patients. Further, curcumin could result in overall improvements in the symptoms such as mouth opening, burning sensation, tongue protrusion, and cheek flexibility in OSMF patients. Curcumin also exhibited strong anticancer and antiangiogenic traits against oral cancer by modulating signaling pathways and inflammatory mediators. Curcumin could also decrease the plaque, inflammation, and gingival index in gingivitis and periodontitis patients. Moreover, toothpaste formulations containing turmeric are also reported for its efficacies in preventing dental plaques and gingivitis by inhibiting various microbes.^241,242

Thus, from the above-mentioned studies, the effectiveness of turmeric and its golden compound curcumin should be considered in the prevention and treatment of several oral diseases. Still, systematic randomized placebo-controlled clinical trials are needed with a large sample size and participants from different ethnic backgrounds to corroborate these results and aid in the clinical paradigm for establishing curcumin as a next-generation smart drug.

Glossary

Abbreviations

ATG5

autophagy related 5

Bax

B-cell lymphoma 2-associated X protein

Bcl-2

B-cell lymphoma 2

BER

base excision repair

CAL

clinical attachment level

C/EBP α

CCAAT/enhancer-binding protein alpha

Cdc 27

cell division cycle protein 27

CDKs

cyclin-dependent kinases

CHX

chlorohexidine

CMS

carboxymethyl starch

COX-2

cyclooxygenase-2

CS

chitosan

CSCs

cancer stem cells

Cur-SLN

curcumin solid-lipid nanoparticle

DMBA

7,12-dimethylbenz(a)anthracene

EGFR

epidermal growth factor receptor

EMT

epithelial mesenchymal transition

ERK

extracellular signal regulating kinase

GI

gingival index

HPV

human papillomavirus

iNOS

inducible nitric oxide synthase

IFN

interferon

IGFBP5

insulin like growth factor binding protein 5

IL

interleukin

LC3

antihuman light chain 3

LPS

lipopolysaccharide

MAPK

mitogen-activated protein kinase

MDSCs

myeloid-derived suppressor cells

MFC

mucoadhesive formulation containing curcumin

MIC

minimum inhibitory concentration

MMP

matrix metalloproteinase

MMT

montmorillonite

MTZ

metronidazole

NF-κB

nuclear factor kappa B

NIK

NF-κB-inducing kinase

NNK

nicotine-derived nitrosamine ketone

Nrf2

nuclear factor erythroid 2-related factor 2

OLP

oral lichen planus

OM

oral mucositis

OPG

osteoprotegerin

OSCC

oral squamous cell carcinoma

OSMF

oral submucous fibrosis

PCNA

proliferating cell nuclear antigen

PD

probing depth

PDL1

programmed death-ligand 1

PGE2-s

prostaglandin E2 synthase

PI

plaque index

PI3K

phosphoinositide 3-kinase

PK

protein kinase

PPAR

peroxisome proliferator-activated receptor

RANK

receptor activator of nuclear factor kappa-B

RANKL

receptor activator of nuclear factor kappa-B ligand

RAS

recurrent aphthous stomatitis

ROM

reactive oxygen metabolites

ROS

reactive oxygen species

RTK

receptor tyrosine kinases

SBI

sulcus bleeding index

SD

Spargue-Dawley

SMA

smooth muscle actin

SOCS

suppressor of cytokine signaling

STAT3

signal transducer and activator of transcription 3

STE

smokeless tobacco extract

SQSTM1

sequestosome-1

TGF-β1

transforming growth factor-β1

TNF-α

tumor necrosis factor-α

VAS

visual analogue scale

VEGF

vascular endothelial growth factor

VL

visible light

4-NQO

4-nitroquinolone-1-oxide

5-FU-OM

5-fluorouracil induced oral mucositis

Author Contributions

^# (S.G., A.K.) These authors contributed equally.

The authors declare no competing financial interest.