Topical Curcumin: A Review of Mechanisms and uses in Dermatology (2023)

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Photo-damaged skin: Actinic keratosis: 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).

  • Topical Curcumin: A Review of Mechanisms and uses in Dermatology (1)

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    Figure 11:
    a. (upper panel): Photo-damaged skin with multiple actinic keratoses vertex scalp before treatment with topical curcumin; b. (lower panel). Improvement of photo-damaged skin and resolution of actinic keratoses after 15 months of concentrated topical curcumin applied twice daily.

    Comment

    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 efficacy 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 benefit, and of biologic plausibility for these benefits from preclinical studies of biologic mechanisms [7,8], there are sufficient grounds to regard topical curcumin as a potential effective therapy for a number of dermatologic disorders [5-11], and as rationale for further clinical trials to evaluate its efficacy.

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    In contrast to the extensive investigations with oral curcumin [4], there have been relatively few reports of preclinical and clinical studies on the therapeutic efficacy of topical curcumin [8,23,32-36]. Most of these were performed on animal models. Partoazar et al. [32], studied the effect of topical curcumin on second degree burns in a rat and found a favorable outcome with its use. Li et al. [33], reported the protective effect of curcumin in ultraviolet light B induced photo-damage in hairless mice and cell cultures. Kant et al. [34], found that topical curcumin hastened wound healing in diabetic rats, while Lopez-Jornet et al. [35], noted that topical curcumin increased healing after carbon dioxide laser damage in mice. In a randomized double-blind placebo-controlled trial performed in patients, Afshariani et al. [36], found topical curcumin to be effective in treating mastitis of breast-feeding women. Kant et al. [37], also proposed that the anti-inflammatory and antioxidant properties of curcumin may be responsible for increased wound healing in diabetic rats. The investigators [47] observed that curcumin decreased TNF-α, IL-1β and MMP-9, and increased superoxide dismutase and catalases in their animals. Kant et al. [37], also found elevated glutathione peroxidase levels, but did not measure reduced glutathione values. Reduced glutathione is usually measured together with superoxide dismutase and catalases in evaluating the anti-oxidant properties of tissues.

    Topical Curcumin may have Pleotropic Effects: In the cases above, we showed clinical benefits of topical curcumin in a fairly diverse variety of dermatologic conditions, including heat related injuries, solar damage and burns, skin wounds, skin healing after surgery, and chronic inflammatory skin conditions like psoriasis, acne, and rosacea. The range of skin conditions that appear to respond to use of topical curcumin suggests that more than one mechanistic effect may be operating with topical curcumin use, i.e. topical curcumin may have pleotropic effects. The extensive literature on biologic effects of curcumin has provided plausible evidence for the potential pleiotropic effects of curcumin [6-8,11-14]. These include its primary effect as a phosphorylase kinase inhibitor [8,23], with particular benefit in psoriasis, and the secondary NF-kB-dependent anti-inflammatory effect that results in improved wound healing and less scarring [8-10,21-23]. The less well-known curcumin-induced apoptosis appear to involve phosphorylase kinase-dependent inhibition of phosphotidylinositol kinase [11-14]. The family of phosphatidylinositol kinases play a key role in the DNA Damage Repair (DDR) pathway [11,24-31], including ATM, ATR which affect Cell Cycle Arrest, Nucleotide Excision Repair, and DNA-protein kinase that is involved in DNA replication. By blocking phosphorylation and repair in this pathway, curcumin induces apoptosis of damaged cells [11-14,24-31]. Although inhibition of phosphorylase kinase may be key in both the anti-inflammatory and anti-apoptotic pathways, other kinases, such as phosphatidylinositol kinases, may also be involved in curcumin-induced apoptosis.

    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 [6-8]. 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 inflammatory process related to wound healing, activating NF-kB which in turn activates 200 genes related to the initiation of inflammation [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 inflammatory 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 significant clinical improvement of psoriasis [8,23].

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    The other chronic inflammatory disorders – rosacea and acne – that involve inflammatory processes that lead to residual scarring [10, 21,22] also appear to respond well to topical curcumin treatment. The beneficial effects of curcumin in these probably result from inhibition of NF-kB-mediated inflammatory response and fibroblastic proliferation, with resultant decrease in residual scarring. Chronic inflammation is a pathophysiologic feature present in acneiform lesions, and the anti-inflammatory effect of topical curcumin is the likely mechanism for results noted with its use. Similarly, the benefits after topical curcumin use after surgical and traumatic injuries, and heat and solar damage, are likely the result of its anti-inflammatory effects. While there are other anti-inflammatory medications available, e.g. topical corticosteroids, the therapeutic benefit 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-inflammatory effects of topical curcumin also appear to reduce fibroblast and myofibroblast 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 [11-14]. 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].

    Newer Strategies involving Nano-encapsulation in Wound healing: Because of its hydrophobic properties, curcumin is known to be poorly absorbed by tissues. For this reason, a host of strategies involving curcumin nano-encapsulation [38-42], have been attempted to increase the effectiveness of delivery of curcumin into tissues for wound healing. These strategies [38-42], include nanovesicles, polymeric micelles, conventional liposomes and hyalurosomes, nanocomposite hydrogels [41], electrospun nanofibers [42], nanohybrid scaffolds [40], nanoconjugates, nanostructured lipid carriers, nanoemulsion, nanodispersion and polymeric nanoparticles [39]. These have yet to be clinically tested in human wounds, and have been mainly studied in hairless mice [41], and diabetic rats [42]. In addition, the long-term benefits and side-effects of each technique are yet to be evaluated.

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    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 compound-target 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 [1-3].

    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 efficacy in dermatologic disorders related to phosphorylase kinase inhibition and secondary downstream NF-kB-mediated anti-inflammatory effects [7-9]. 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 find 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.

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    Disclosures

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

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