Molecular Mechanisms of Melanocyte Activation in Solar Lentigos and Their Rational Therapeutic Treatments

To characterize the pathobiology of solar lentigos (SLs), analyses by semiquantitative RT-PCR,
western blotting and immunohistochemistry revealed the up-regulated expression of endothelin
(EDN)-1/endothelin B receptor (EDNBR), stem cell factor (SCF)/c-KIT and tumor necrosis factor
(TNF) in the lesional epidermis, which contrasted with the down-regulated expression of interleukin
(IL) 1. These findings strongly supported the hypothesis that unknown tumorigenic factors due to
possible cumulative DNA damage caused by previous repeated UVB exposures triggers keratinocytes
to continuously produce TNF. TNF then stimulates the secretion of EDNs and the production of
SCF in an autocrine fashion, leading to the continuous melanogenic activation of neighboring
melanocytes, which causes SLs. Since the EDN signaling cascade is specifically associated with the
protein kinase C pathway, which involves intracellular calcium mobilization, we screened biological
extracts for inhibitory effects on EDN1-induced calcium mobilization, and identified an extract of
Matricaria chamomilla that has a potent ability to abrogate the EDN1-induced increase in DNA
synthesis and melanization of human melanocytes in culture. A clinical study of 36 patients with SLs
for 6 months treated with the M. Chamomilla extract revealed a significant improvement in pigment
scores and color differences expressed as L values. To further characterize the effects of a proven
whitening agent, L-ascorbate -2-phosphate 3 Na (APS), we conducted a double-blind half face study
of 27 Japanese female volunteers with SLs. That clinical study demonstrated that L values of test
lotion (6% APS)-treated skin significantly increased in SLs and in non-lesional skin with a significantly
higher ΔL value in SLs compared with non-lesional skin. The sum of these findings strongly suggests
that combined treatment with EDN signaling blockers and tyrosinase inhibitors is a desirable
therapeutic choice for SLs.