Topical Curcumin: A Review of Mechanisms and uses in Dermatology

Curcumin, the active ingredient in the spice turmeric, has been used in many Eastern countries for its known anti-infl ammatory activity. Recently, analysis of multiple studies have cast doubt with regard to the effi cacy of oral curcumin in several diseases. While the effectiveness of oral curcumin is hindered by its low bioavailability and poor absorption by the oral route, this is not the case for topical curcumin. In this review, we discuss the mechanisms for its anti-infl ammatory and anti-apoptotic activity based on its inhibitory activity on the enzyme, phosphorylase kinase, and present evidence for its salutary effects on burns, wounds, surgical scars, photo-damaged skin and psoriasis. Review Article Topical Curcumin: A Review of Mechanisms and uses in Dermatology Madalene CY Heng* Professor of Medicine/Dermatology, UCLA School of Medicine, USA Dates: Received: 19 April, 2017; Accepted: 05 July, 2017; Published: 06 July, 2017 *Corresponding author: Madalene C.Y. Heng, Professor of Medicine/Dermatology, UCLA School of Medicine, USA, E-mail: https://www.peertechz.com


Introduction
Curcumin (diferuloylmethane) is one of the ingredients found in the spice, turmeric. Turmeric has been used for centuries in many Eastern countries both as a spice and as a medicine. In recent years, extensive studies have been done on the potential medicinal value of curcumin, particularly when taken orally. The effectiveness of oral curcumin, however, is hindered by poor bioavailability because the unconjugated curcumin molecule, which is hydrophobic, is poorly absorbed by the gastrointestinal tract. Very low curcumin levels are detected in blood and tissues following curcumin ingestion [1][2][3]. The molecule is mainly absorbed as water-soluble curcumin glucoronate or sulfate metabolites, which are largely inactive products. In contrast, topical curcumin can be formulated to be better absorbed through the skin, particularly when the skin barrier becomes defective in the presence of skin injury and disease. Largely because of the unfavorable pharmacokinetics of oral curcumin, the extensive literature on therapeutic potential of oral curcumin in clinical trials has been disappointingly negative [4]. There have been much fewer studies with topical curcumin despite the fact that the use of topical curcumin is not hindered by issues of gastrointestinal absorption.
In this review, we will present our clinical experience with topical curcumin in several dermatologic disorders, and discuss the mechanisms that may underlie the biologic basis of how topical curcumin may potentially be useful in these conditions. We found topical curcumin to be effective in a number of conditions associated particularly with skin injury and infl ammation. We believe that the most likely mechanism responsible for these results is related to the unique ability of curcumin to inhibit the enzyme, phosphorylase kinase. In addition, topical preparations can be more easily formulated to increase penetration of the hydrophobic curcumin through the skin, unlike the problems encountered with curcumin bioavailability in the gut. Skin penetration of topical curcumin may also be enhanced in dermatologic disorders because of infl ammation and loss of the normal skin barrier function.
These factors make the potential therapeutic value of topical curcumin much more promising than that found so far with oral curcumin.

Anti-infl ammatory Properties
Curcumin is widely known to have anti-infl ammatory properties [5]. In cell cultures, it has been shown to suppress the proliferation of a wide variety of tumor cells, downregulate transcription factors (NF-kB, AP-1), downregulate the expression of cytokines (TNF-), cell surface adhesion molecules and cyclin D, and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinase, and protein serine/ threonine kinases [5].
How curcumin may have therapeutic benefi ts became better understood after discovery that curcumin is a selective inhibitor of phosphorylase kinase [6], Phosphorylase kinase is an enzyme responsible for breaking down glycogen, eventually to form ATP, and plays an important role in phosphorylation reactions [7]. Phosphorylase kinase is released within 5 mins after injury and plays a key role in the injury pathway with signifi cant effect on activation of infl ammatory cells [7][8][9], wound healing and scar tissue formation [10]. Inhibition of phosphorylase kinase activity by curcumin results in modulation of the infl ammatory response because of downregulation of transcription factors, DOI: http://doi.org/10.17352/2455-8605.000020 cytokines, adhesion molecules, cyclin kinases, and a variety of protein kinases.

Curcumin-Induced apoptosis
Curcumin has been reported to induce apoptosis in damaged cells [11][12][13]. The process may allow more rapid replacement of the injured cells by normal healthy cells [11].
This may be the mechanism for our clinical observations of improved healing of burns and sun-burns. Curcumin-induced apoptosis may also function in the improvement observed with the application of curcumin gel on sun-damaged skin.
The removal of damaged premalignant cells by apoptosis allows the space for replacement by new, healthy cells without the potential of malignant transformation [11]. By blocking phosphorylation, curcumin may block the DNA Damage Repair (DDR) pathway through histone-mediated DNA repair, and as a consequence, accelerate apoptosis [11]. Curcumin-mediated apoptosis has been shown to occur through the mediation of the mitochondrial pathway [12].
The mechanism of curcumin-induced apoptosis may also be achieved by inhibition of phosphorylase kinase. Georgoussi et al., has reported that phosphorylase kinase also exhibits phosphatidylinositol kinase activity [14]. This is signifi cant since the early participants in the DDR pathway include a family of phosphatidylinositol kinases responsible for Cell Cycle Arrest, Nucleotide Excision and Repair and DNA replication [11].
It is probable that curcumin induces apoptosis by blocking phosphorylation of the phosphatidylinositol kinases through phosphorylase kinase inhibition.

Response:
The key molecule in the tissue injury pathway ( Figure 1) is a transcription activator, nuclear factor-kB, which is expressed as early as 30 mins after injury [15,16].
In the non-activated state, NF-kB exists as a pair of dimers (p50/p65) within the cytoplasm. When activated by injury, phosphorylation occurs at several serine specifi c sites (Ser276; Ser529, Ser536), and the dimers translocate to the nucleus, where they bind to the kB site on the DNA, resulting in turning on over 200 genes related to infl ammation, cell migration, cell cycling, and cell proliferation [7][8][9][10]. Before the dimers are able to translocate to the nucleus, the inhibitory molecule, IkB is removed, and the removal requires the activation of its kinase, IkB kinase. Activation of the IkB kinase requires phosphorylation of both serine (Ser171, Ser181) and tyrosine (Tyr188, Tyr199) moieties [7][8][9][10]. Phosphorylation of both Serine and Tyrosine moieties is achieved by the dual specifi city kinase, phosphorylase kinase.
Phosphorylase Kinase: A Dual-Specifi city Kinase/Multispecifi city Kinase: Protein kinases usually catalyze the transfer of high energy phosphate bonds to either serine/threonine or tyrosine moieties. This is because protein kinases, with the exception of phosphorylase kinase, allow only one confi guration in their substrate binding site. In the case of phosphorylase kinase, however, the substrate binding site may be altered by utilizing a hinge joint between the subunits to alter the size of the substrate binding site. In addition, the substrate binding site may be made to alter its shape and swivel in one plane by binding to magnesium, or in another by binding to manganese.
In this way, phosphorylase kinase is able to phosphorylate substrates of multiple specifi cities i.e. both serine/threonine and tyrosine. Graves [17], reported that in the phosphorylase kinase molecule, the spatial arrangement of the specifi city determinants can be manipulated so that phosphorylase kinase can utilize several substrates. Yuan et al. [18], provided evidence of dual specifi city of phosphorylase kinase, depending on ion binding i.e., manganese or magnesium. There is evidence that phosphorylase kinase also activates phosphatidylinositol kinase [14].

Curcumin, a Selective Phosphorylase Kinase Inhibitor:
Curcumin has been shown to be a selective, non-competitive phosphorylase kinase inhibitor [6]. By inhibiting phosphorylase kinase in the injury pathway, curcumin blocks the activation of NF-kB, the transcription activator [5,19,20]. NF-kB is responsible for activating 200 genes related to proliferation of infl ammatory cells (T cells and macrophages), cell migration, cell cycling (including cyclin D), epidermal proliferation and fi broblast proliferation. The growth factor (TGF1) secreted by macrophages is responsible for conversion of fi broblasts to myofi broblasts, which are responsible for hypertrophic scarring [10,21,22]. Blocking the activation of NF-kB-mediated TGF-beta1 is likely to be mechanistically relevant to the therapeutic effi cacy of topical curcumin in skin injury and healing.

Clinical effects of topical curcumin in skin disorders
Acute Injury: Burns, Wounds and Surgical Scars: We have observed that topical curcumin can be used to heal acute skin injuries more rapidly, often with less or no scarring. The cases presented include burns, wounds and surgical wounds.
Burns from a Barbeque Fire: Figure 2a shows a patient who sustained secondary degree burns after pouring lighter fl uid on a barbeque fi re. He was engulfed in fl ames and sustained burns over his forehead, eyelids, cheeks, ears, nose, lips and neck. He also singed his hair and eyelashes. He was seen 4 days after

NF-kB (30 mins) T cells, macrophages (hours to days) Cell Proliferation
Fibroblast proliferation (one week); scar Myofibroblast proliferation (2 weeks); hypertrophic scar   (right panels). When seen many months later, the fi nger had healed completely without scarring, nerve dysfunction or nail dystrophy.   Figure  7a (left panels) shows a acne patient with severe follicular plugging. She was put on a regimen aimed at unplugging the plugged follicles with high dose oral vitamin A (100,000 IU tid) for 9 months, retinoic acid gel 0.025% at bed-time and curcumin gel during the day. For control of the pustules, she was put on oral minocycline 100 mg daily. Curcumin gel helped healing without residual scarring. Figure 7b (right panels) show signifi cant improvement after 12 months of treatment.

Improvement of Scarring in Acneiform Conditions:
Psoriasis: Psoriasis is a genetic disease with lesions usually precipitated by injury (trauma, allergic contact allergens and bacterial superinfection). Psoriatic activity has been associated with elevated levels of phosphorylase kinase [7]. Suppression of phosphorylase kinase by topical curcumin has been shown to correlate with resolution of psoriasis [8]. We have developed a protocol aimed at inhibition of phosphorylase kinase activity [23]. by the use of topical curcumin, avoidance of contact allergens, treatment of bacterial infections and avoidance of lactose in the diet. Figure 8 shows a patient with chronic psoriasis for 60 years, aggravated by black hair dye and clothing dye allergy, elastic underwear, MRSA infection and lactose intolerance. Figure 8a,b (left panels) show the patient with generalized psoriasis before treatment with the protocol, and fi gure 8c,d (right panels) show complete clearance following 16 weeks of treatment including intravous vancomycin, clobetasol solution 0.05% for the scalp., clobetasol cream 0.05% mixed with ketoconazole cream 2% for the trunk and limbs during the day, and topical curcumin gel in the evenings. She was also put on oral Difl ucan 200 mg weekly for candida intertrigo, lactose free diet and daily bleach baths. Figure 8c,d (right panels) show complete clearance after 16 weeks fo treatment with no recurrence for many years.

Sunburns and photo-damaged skin
Ultraviolet light (both UVA and UVB) induces the formation of cyclobutane pyrimidine dimers (CPDs) which damage the     [24][25][26][27]. Mistakes are made when large segments of the DNA are involved, or when both strands of DNA are affected. The DNA repair pathway involves a family of phosphatidylinositol kinases [28][29][30][31]. These are involved in Cell Cycle Arrest CCA), Nucleotide Excision Repair (NER) and replacement by newly synthesized nucleotide strands. The repair mechanisms involving the DNA Repair Pathway [25][26][27][28], are laborious and slow [11], with residual damaged cells resulting in a potential for tumor transformation. Topical curcumin, by induction of curcumin-induced apoptosis [11][12][13][14], results in the rapid repair of sun-burns, leaving space necessary for replacement by normal cells without malignant potential. This may prevent or potentially reduce future development of premalignant and malignant lesions.

Sunburns:
Although UVB rays have less penetrating property and usually do not cause basal cell carcinomas and malignant melanomas, they do cause painful sunburns. Figure  9a (upper panel) showed severe sunburn with early blistering. The burns were much improved two days later with frequent applications of topical curcumin (Figure 9b (lower panel). Figure 10a (upper panel) shows photo-damaged skin (actinic dermatitis) with multiple confl uent actinic keratoses involving the ear. He had previous surgery for squamous cell carcinoma. After the use of concentrated topical curcumin for over a year, there was improvement with signifi cant resolution of his photo-damaged skin (Figure 10b (lower panel). Figure 11 shows photo-damaged skin with multiple actinic keratoses over the vertex scalp (upper panel). After 15 months of concentrated curcumin gel, there was resolution of the actinic keratoses and improvement in the surrounding photo-damaged skin ( Figure  10b -lower panel).

Therapeutic effects of topical curcumin
In the above discussion, we show examples of the clinical effects of topical curcumin on a spectrum of dermatologic conditions. We emphasize these are clinical cases treated with topical curcumin usually in association with other standard therapy, including antibiotics. They were not part of a protocol designed to systematically investigate the clinical effi cacy of topical curcumin. Instead, we used them as examples of results in our experience with the goal of informing other investigators of the potential therapeutic value of topical curcumin, and to encourage future proof of concept studies into its use for skin disorders. We believe that from the viewpoint of having preliminary proof of clinical benefi t, and of biologic plausibility for these benefi ts from preclinical studies of biologic mechanisms [7,8], there are suffi cient grounds to regard topical curcumin as a potential effective therapy for a number of dermatologic disorders [5][6][7][8][9][10][11], and as rationale for further clinical trials to evaluate its effi cacy.
In our clinical experience and studies, topical curcumin is an effective therapy for psoriasis [8,23], an observation that is likely related to curcumin being a potent and selective inhibitor of phosphorylase kinase [6][7][8]. Our previous laboratory and clinical studies have suggested that psoriatic patients may have a defective mechanism, genetic in origin, in switching off phosphorylase kinase activity after the enzyme has been activated by injury [8,23]. Phosphorylase kinase plays a crucial role in the infl ammatory process related to wound healing, activating NF-kB which in turn activates 200 genes related to the initiation of infl ammation [5,9,10,19,20]. Activation of NF-kB has been shown to be blocked by curcumin [19,20]. Our studies suggest that psoriatic patients may have a genetic defect that results in the inability to switch off phosphorylase kinase, and accordingly, an inability to reduce the infl ammatory process triggered by external precipitating or aggravating factors [7,8,23]. The clinical result is the development of psoriatic lesions that tend to persist rather than heal. We have reported that inhibition of phosphorylase kinase activity by topical curcumin results in decreased phosphorylase kinase activity and signifi cant clinical improvement of psoriasis [8,23].
The other chronic infl ammatory disorders -rosacea and acne -that involve infl ammatory processes that lead to residual scarring [10,21,22] also appear to respond well to topical curcumin treatment. The benefi cial effects of curcumin in these probably result from inhibition of NF-kB-mediated infl ammatory response and fi broblastic proliferation, with resultant decrease in residual scarring. Chronic infl ammation is a pathophysiologic feature present in acneiform lesions, and the anti-infl ammatory effect of topical curcumin is the likely mechanism for results noted with its use. Similarly, the benefi ts after topical curcumin use after surgical and traumatic injuries, and heat and solar damage, are likely the result of its anti-infl ammatory effects. While there are other anti-infl ammatory medications available, e.g. topical corticosteroids, the therapeutic benefi t of topical curcumin lies in its safety and absence of observable side-effects. The clinical outcome of the use of topical curcumin on surgical scars and wounds are of particular interest. In our clinical experience, we observed that surgical wounds healed more rapidly and with less scarring with topical curcumin than without [10]. The anti-infl ammatory effects of topical curcumin also appear to reduce fi broblast and myofi broblast formation in surgical wounds, with less scarring and keloid formations [10].
Studies showing that curcumin induces apoptosis in damaged cells show yet another aspect of the curcumin pleiotropy [11][12][13][14]. This mechanism may assist wound healing in accelerating removal of dead or dying cells and replacement by normal ones. We observed more rapid healing in traumatic wounds and heat or solar damage which may, in part, be due to this property of the curcumin [11].

Topical versus Oral Curcumin:
The use of curcumin for medicinal purpose has long been deeply embedded in many Eastern cultures, most prominently in South Asia. Mainly because of this, curcumin has been the focus of extensive studies into its possible medicinal value for a wide variety of diseases. The comprehensive review by Nelson et al. [4], reported that in 2015, the Curcumin Resource Database listed over 9000 publications and 500 patents on potential therapeutic value curcumin for a number of unrelated diseases. The great majority of these were related to studies with oral curcumin. The review noted that despite over 120 clinical trials of curcumin done, no double-blinded, placebo controlled trial has been reported successful [4]. There appears to be at least two important reasons for this. Curcumin has been demonstrated to be an unstable, reactive compound that interferes with assay readout, providing a misleading experimental outcome from this false activity rather than through real compoundtarget interaction [4]). Many of the preclinical studies showing initial promise that led to the unsuccessful clinical trials were attributed to this phenomenon. Probably more importantly, oral curcumin is poorly absorbed and has very low bioavailability, which essentially renders curcumin a poor candidate as an effective oral agent [1][2][3].
The issues detailed above with oral curcumin do not appear applicable to topical curcumin. Both the interference with assay readout encountered after oral curcumin and low bioavailability were not reported in the context of topical curcumin use. The negative results of clinical trials with oral curcumin are also unlikely to be pertinent to topical curcumin because the pharmacology and therapeutics of oral and topical medications are extremely different. In addition, our studies with topical curcumin suggest biologic mechanisms for topical curcumin effi cacy in dermatologic disorders related to phosphorylase kinase inhibition and secondary downstream NF-kB-mediated anti-infl ammatory effects [7][8][9]. We postulate that these effects are highly plausible biologic mechanism for the clinical improvement noted after topical curcumin use in the cases presented above.
It is clear from the extensive literature on curcumin that oral administration of curcumin is not likely to be productive in the search for new medicinal products from the compound. Instead, the search should be changed to fi nd uses for curcumin without the need for systemic absorption. Nelson et al. [4], suggested "As an alternative approach, it may be possible for compound 1 (i.e. curcumin) to have an effect on human health without being absorbed" [4]. While the authors referred to its use for gastrointestinal disorders, we believe that it is just as important, and also because it may be more productive, that topical curcumin be investigated more extensively in skin disorders.

Disclosures
Dr. Heng has shares in Omnicure, Inc., a company that manufactures and markets topical curcumin gel.