Diphlorethohydroxycarmalol inhibits melanogenesis via protein kinase A/cAMP response element‐binding protein and extracellular signal‐regulated kinase‐mediated microphthalmia‐associated transcription factor downregulation in α‐melanocyte stimulating hormone‐stimulated B16F10 melanoma cells and zebrafish

Abstract

Diphlorethohydroxycarmalol (DPHC) is a marine polyphenolic compound derived from brown alga Ishige okamurae. A previously study has suggested that DPHC possesses strong mushroom tyrosinase inhibitory activity. However, the anti‐melanogenesis effect of DPHC has not been reported at cellular level. The objective of the present study was to clarify the melanogenesis inhibitory effect of DPHC and its molecular mechanisms in murine melanoma cells (B16F10) and zebrafish model. DPHC significantly inhibited tyrosinase activity and melanin content dose‐dependently in α‐melanocyte stimulating hormone (α‐MSH)‐stimulated B16F10 cells. This polyphenolic compound also suppressed the expression of phosphorylation of cAMP response element‐binding protein (CREB) by attenuating phosphorylation of cAMP‐dependent protein kinase A, resulting in decreased MITF expression levels. Furthermore, DPHC downregulated MITF protein expression levels by promoting the phosphorylation of extracellular signal‐regulated kinase. It also inhibited tyrosinase, tyrosinase‐related protein 1 (TRP‐1), and TRP‐2 in α‐MSH stimulated B16F10 cells. In in vivo studies using zebrafish, DPHC also markedly inhibited melanin synthesis in a dose‐dependent manner. These results demonstrate that DPHC can effectively inhibit melanogenesis in melanoma cells in vitro and in zebrafish in vivo, suggesting that DPHC could be applied in fields of pharmaceutical and cosmeceuticals as a skin‐whitening agent. Significance of study: The present study showed for the first time that DPHC could inhibit a‐MSH‐stimulated melanogenesis via PKA/CREB and ERK pathway in melanoma cells. It also could inhibit pigmentation in vivo in a zebrafish model. This evidence suggests that DPHC has potential as a skin whitening agent. Taken together, DPHC could be considered as a novel anti‐melanogenic agent to be applied in cosmetic, food, and medical industry.

Syringetin Promotes Melanogenesis in B16F10 Cells

“…The MAPK family, including ERK, JNK, and p38 MAPK, has been shown to play a crucial role in melanogenesis. Although ERK and JNK have been implicated in regulating melanin production, the overall role of MAPK pathway activation in melanin synthesis remains controversial [ 19 , 20 ]. In B16 melanoma cells, theophylline enhances melanin production by increasing ERK phosphorylation, whereas it has been demonstrated that increasing p-ERK levels suppresses melanogenesis [ 23 ].…”

“…Consequently, modulating the MAPK signaling pathway represents a potential approach to controlling melanogenesis. Results depicted in Figure 5 Mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular signalregulated kinase (ERK), and c-Jun N-terminal kinase (JNK), have been implicated in MITF expression regulation [19,20]. Additionally, several signaling pathways, such as ERK, p38, and phosphatidylinositol 3-kinase (PI3K)/AKT, have been linked to melanin synthesis regulation [21,22].…”

“…The mitogen-activated protein kinase (MAPK) family proteins ERK, JNK, and p38 MAPK also play crucial roles in melanogenesis. Phosphorylation of p38 and JNK can induce MITF expression, whereas phosphorylation of ERK inhibits melanin synthesis [ 19 , 20 ]. Additionally, the PI3K/Akt signaling pathway has been identified as regulating melanogenesis through MITF expression and subsequent expression of tyrosinase, TRP-1, and TRP-2 [ 21 , 22 ].…”

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…Other tested compounds using zebrafish models were recently demonstrated to possess antimelanoma potential. Among them are diphlorethohydroxycarmalol [286], theaflavin [287], ellagic acid [288], inularin [289], and BEL β-trefoil [290].…”