Development of Pigmentation-Regulating Agents by Drug Repositioning

Abstract

Skin color is determined by the processes of melanin synthesis and distribution. Problems in various molecules or signaling pathways involved in melanin synthesis contribute to skin pigmentation defects. Several trials have been conducted on the production of pigmentation-regulating agents, and drug repositioning has emerged as a modern technique to identify new uses for existing drugs. Our research team has researched substances or drugs associated with pigmentation control and, as a result, nilotinib, sorafenib, and ICG-001 have been found to promote pigmentation, while 5-iodotubercidin inhibits pigmentation. Therefore, these substances or medications were suggested as potential therapeutics for pigmentation disorders by drug repositioning.

Keywords: drug repositioning; melanogenesis; signaling pathways.

Figure 1

The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.

Figure 2

Core signaling pathways associated with the regulation of melanogenesis in melanocytes. Genes encoding specific melanogenic enzymes, including tyrosinase and TRPs, are regulated by the MITF transcription factor, which is consequently regulated by a number of signaling pathways, including α-MSH/MC1R (orange), SCF/KIT (blue) and Wnt/frizzled (purple). Signal transduction is mediated by cAMP/PKA, RAS/MAPK and β catenin pathways. The cholinergic system is a negative regulator of melanogenesis. ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptor; α-MSH, α-melanocyte-stimulating hormone; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated protein kinase; GSK3β, glycogen synthase kinase 3β; c-KIT, tyrosine kinase receptor; MAPK, mitogen-activated protein kinase; MC1R, melanocyte-specific melanocortin 1 receptor; MITF, microphthalmia-associated transcription factor; PKA, protein kinase A; PI3K, phosphatidylinositol 3-kinase; SCF, stem cell factor; TRPs, tyrosinase-related proteins; Wnt, wingless-related integration site.

Figure 3

Proposed mechanism of nilotinib in the regulation of pigmentation. Nilotinib enhances melanogenesis by inhibiting phospho-AKT and activating cAMP/PKA.

Figure 4

Proposed mechanism of sorafenib in the regulation of pigmentation. Sorafenib enhances melanogenesis by inhibiting phospho-AKT and phospho-ERK and activating β-catenin.

Figure 5

Proposed mechanism of 5-iodotubercidin in inhibiting effects of pigmentation. 5-Iodotubercidin inhibits melanogenesis by inhibiting cAMP/PKA and activating phospho-AKT.