Topical Application of a Protein Kinase C Inhibitor Reduces Skin and Hair Pigmentation

Abstract

To determine whether inhibition of PKC-beta activity decreases pigmentation, paired cultures of primary human melanocytes were first pretreated with bisindolylmaleimide (Bis), a selective PKC inhibitor, or vehicle alone for 30 min, and then treated with TPA for an additional 90 min to activate PKC in the presence of Bis. Bis blocked the expected induction of tyrosinase activity by activation of PKC. Addition of a peptide corresponding to amino acids 501-511 of tyrosinase containing its PKC-beta phosphorylation site, a presumptive PKC-beta pseudosubstrate, gave similar results. To determine whether Bis reduces pigmentation in vivo, the backs of four shaved and depilated pigmented guinea pigs were UV irradiated with a solar simulator for 2 wk excluding weekends. Compared to vehicle alone, Bis (300 microM), applied twice daily to paired sites for various periods encompassing the irradiation period, decreased tanning. Bis also, although less strikingly, reduced basal epidermal melanin when topically applied twice daily, 5 d per wk, for 3 wk to shaved and depilated unirradiated skin. Moreover, topical application of Bis (100 microM) once daily for 9 d to the freshly depilated backs of 8-wk-old mice markedly lightened the color of regrowing hair. These results demonstrate that inhibiting PKC activity in vivo selectively blocks tanning and reduces basal pigmentation in the epidermis and in anagen hair shafts.

Specifying protein kinase C functions in melanoma

“…The function of PKCb in melanin biosynthesis is linked to its ability to phosphorylate and activate tyrosinase, the rate-limiting enzyme in melanin production (Park et al, 1999(Park et al, , 2004b. Consistent with this, PKC activators can stimulate melanocyte pigmentation and PKC inhibitors block pigment production in mouse skin (Park et al, 1993(Park et al, , 2004a. Selectivity for PKCb phosphorylation of tyrosinase on melanosomes is dependent on the anchoring protein RACK1 (Park et al, 2004b;Stebbins and Mochly-Rosen, 2001).…”

Effect of Adipose-Derived Stem Cells on Induced Photoaging in the Skin of Adult Guinea Pig: Histological and Immunohistochemical Study

“…Each session of exposure to irradiation lasted approximately 15 minutes with an irradiation dose of 150 mJ/ cm2. Under these conditions, guinea pigs did not show any erythema, edema, or scaling [21] .…”

Peptide‐Based Inhibitors of Enzymes

“…Tyrosinase activation is accomplished through PKC-on a phosphorylation site within a C-terminal sequence of 11 amino acids [127,128]. An 11-mer tyrosinase mimetic peptide has been shown to be an effective inhibitor of PKCbinding, resulting in decreased tyrosinase phosphorylation [129]. Another effective tyrosinase inhibitor is kojic acid, a fungal metabolite widely used as a cosmetic skin-lightening agent or food additive for antibrowning effect.…”