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

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.

UVR Promotes Keratinocyte Phagocytosis and Skin Pigmentation Through TRPA1 Channels

“…1 In the process of melanosome transfer, keratinocyte phagocytosis has recently been 1190 considered as a crucial section. 24 Notably, a recent study suggested that melanocores (the melanin core devoid of surrounding membrane) were internalized by phagocytosis, whereas melanosomes (melanin core with intact surrounding membrane) were internalized by macropinocytosis in keratinocytes. 25 In this study, we confirmed that UVR enhanced the phagocytic ability of keratinocytes, which was regulated by TRPA1.…”

The Inhibitory Effect of Curcumin Derivative J147 on Melanogenesis and Melanosome Transport by Facilitating ERK-Mediated MITF Degradation

“…The therapeutic use of curcumin and chemically modified curcumin (CMC) for inhibiting tyrosinase activity and melanin formation has been reported recently ( Goenka and Simon, 2021 ). However, the poor bioavailability of curcumin and chemically modified curcumin (CMC) limits its application ( Karthikeyan et al, 2020 ).…”

“…The regulation of melanosome transfer from melanocytes to neighboring keratinocytes is an important mechanism for skin whitening. Recently, Goenka et al reported that chemically modified curcumin analogs suppressed dendricity in melanocytes and inhibited the phagocytosis of FluoSphere beads (melanosome mimics) by HaCaT cells ( Goenka and Simon, 2021 ). The present study expanded upon previous studies and demonstrated that J147 inhibited melanosome transfer to neighboring keratinocytes in the keratinocyte/melanocyte co-culture system ( Figure 3A ).…”

Comparative Study of Δ9-Tetrahydrocannabinol and Cannabidiol on Melanogenesis in Human Epidermal Melanocytes from Different Pigmentation Phototypes: A Pilot Study

“…HEMn-LP cells (1.5 × 10 5 cells/well) or HEMn-DP cells (1.2 × 10 5 cells/well) were cultured in 6-well plates for 24 h followed by the addition of test compounds and further cultured for 6 d. The relative levels of cellular melanin were determined in a manner similar to the method reported in previous studies [ 30 , 31 ]. Briefly, the cells were harvested, washed in PBS, and 150 μL of 1 N NaOH was added and heated to 70 °C to solubilize melanin.…”

“…After the treatments, random microscopic fields in each well were imaged at 20× objective magnification. The images were analyzed using an NIS Elements computer-aided image analyzer and two parameters, (i) number of dendrites and (ii) total dendrite length, were quantified in a manner similar to the method reported in previous studies [ 30 , 33 ]. HEMn-DP (3.8 × 10 4 cells/well) was seeded in a 6-well plate for 48 h and compounds was then added for 6 d, and similar measurements were performed.…”