Novel Chemically Modified Curcumin (CMC) Analogs Exhibit Anti-Melanogenic Activity in Primary Human Melanocytes.

Shilpi Goenka,Sanford R. Simon

doi:10.3390/ijms22116043

Abstract

Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.

Highlights

Our results showed that CMC2.14 induced significant cytotoxiranges for all chemically modified curcumin (CMC)
Our results showed that CMC2.14 induced significant cytotoxicity at city at 20 and 25 μM, while it stimulated proliferation of HaCaT cells at lower concentra20 and 25 μM, while it stimulated proliferation of HaCaT cells at lower concentrations of 5 tions of 5 and 10 μM (Figure 1B)
Our results showed that as expected, CMC2.24 (10 μM) significantly inhibited the tyrosinase activity in HEMn-DP cells by 52.77% while CMC2.23 (20 μM)

Summary

Introduction

Melanocytes reside in the stratum basale layer of the epidermis and participate in the protection of skin from the damaging effects of UV light on DNA of keratinocytes by transferring melanin containing melanosomes from the melanocytes to keratinocytes in a parasolic arrangement around their nucleus [1]. Melanocytes connect to neighboring keratinocytes in the epidermis by dendrites; one melanocyte contacts up to 30–40 keratinocytes to transfer melanin [3]. For the efficient export of melanosomes by melanocytes, both the dendrite length and number of dendrites are critical components, as melanocytes can branch out by increasing their number of dendrites to contact multiple keratinocytes that are in close proximity and can elongate their dendrites to export pigment to multiple keratinocytes surrounding them in the suprabasal layers of the epidermis. The inhibition of melanosome export is emerging as a novel target when designing inhibitors of excessive pigmentation and a large number of reports [6,7,8,9], including our previous studies [10,11,12], have described compounds which can inhibit dendricity and have the potential to suppress export of melanosomes

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