Anti-Melanogenesis Effects of a Cyclic Peptide Derived from Flaxseed via Inhibition of CREB Pathway

Abstract

Linosorbs (Los) are cyclic peptides from flaxseed oil composed of the LO mixture (LOMIX). The activity of LO has been reported as being anti-cancer and anti-inflammatory. However, the study of skin protection has still not proceeded. In particular, there are poorly understood mechanisms of melanogenesis to LO. Therefore, we investigated the anti-melanogenesis effects of LOMIX and LO, and its activity was examined in mouse melanoma cell lines. The treatment of LOMIX (50 and 100 μg/mL) and LO (6.25–50 μM) suppressed melanin secretion and synthesis, which were 3-fold increased, in a dose-dependent manner, up to 95%. In particular, [1–9-NαC]-linusorb B3 (LO1) and [1-9-NαC]-linusorb B2 (LO2) treatment (12.5 and 25 μM) highly suppressed the synthesis of melanin in B16F10 cell lines up to 90%, without toxicity. LOMIX and LOs decreased the 2- or 3-fold increased mRNA levels, including the microphthalmia-associated transcription factor (MITF), Tyrosinase, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2) at the highest concentration (25 μM). Moreover, the treatment of 25 μM LO1 and LO2 inhibited the expression of MITF and phosphorylation of upper regulatory proteins such as CREB and PKA. Taken together, these results suggested that LOMIX and its individual LO could inhibit melanin synthesis via downregulating the CREB-dependent signaling pathways, and it could be used for novel therapeutic materials in hyperpigmentation.

Anticancer Potential of the Cyclolinopeptides

“…Contrary to expectations, CLP-A and CLP-B only reduced the pigmentation in the cells without any cytotoxic effect on melanoma cells. The same effect was observed once CLP-A, CLP-B, CLP-D, CLP-E, CLP-F, and CLP-G were mixed [34]. A possible explanation for this effect may be a low concentration of the applied CLPs, as only concentrations of 25 to 100 µg/mL have been used [34].…”

“…The same effect was observed once CLP-A, CLP-B, CLP-D, CLP-E, CLP-F, and CLP-G were mixed [34]. A possible explanation for this effect may be a low concentration of the applied CLPs, as only concentrations of 25 to 100 µg/mL have been used [34]. Some experiments conducted in the past showed that cytotoxic effects would start at concentrations of at least 200 µg/mL.…”

“…In addition, no reported study examines the effect of CLPs in cancer induction and experimental animal models. All the experiments carried out on CLPs are in vitro studies, wholly based on cell cultures [13,21,[31][32][33][34][35][36]. Some studies regarding CLPs and anti-inflammatory effects primarily include mouse models [37,38].…”

“…The next cancer type for which the toxicity of CLPs was examined was melanoma [33,34]. Melanoma originates from the melanocytes and represents the most lethal form of skin cancer [44].…”

“…Another study that involved melanoma and the effect of CLPs on melanogenesis was conducted in 2022 [34]. For this purpose, mouse-derived B16-F10 melanoma cells were used.…”