Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts

Abstract

Background:There is growing evidence that 5-fluorouracil (5-FU) combined with therapeutic trauma can effectively induce skin repigmentation in vitiligo patients who are unresponsive to conventional treatments. Previous studies have mainly focused on identifying the antimitotic activity of 5-FU for the treatment of skin cancer, but few studies have investigated its extra-genotoxic actions favoring melanocyte recruitment.Methods:We utilized the full thickness excisional skin wound model in Dct-LacZ transgenic mice to dynamically assess the migration of melanocytes in the margins of wounds treated with or without 5-FU. The in-situ expression of CXCL12 was examined in the wound beds using immunofluorescence staining. Quantitative real-time polymerase chain reaction and Western blotting analyses were performed to detect the expression levels of CXCL12 mRNA and protein in primary mouse dermal fibroblasts treated with or without 5-FU. Transwell assays and fluorescein isothiocyanate (FITC)-phalloidin staining were used to observe cell migration and filamentous actin (F-actin) changes of melan-a murine melanocytes.Results:Whole mount and cryosection X-gal staining showed that the cell numbers of LacZ-positive melanocytes were much higher in the margins of dorsal and tail skin wounds treated with 5-FU compared with the controls. Meanwhile, CXCL12 immunostaining was significantly increased in the dermal compartment of wounds treated with 5-FU (control vs. 5-FU, 22.47 ± 8.85 vs. 44.69 ± 5.97, P < 0.05). Moreover, 5-FU significantly upregulated the expression levels of CXCL12 mRNA (control vs. 5-FU, 1.00 ± 0.08 vs. 1.54 ± 0.06, P < 0.05) and protein (control vs. 5-FU, 1.00 ± 0.06 vs. 2.93 ± 0.10, P < 0.05) in cultured fibroblasts. Inhibition of the CXCL12/CXCR4 axis suppressed melanocyte migration in vitro using a CXCL12 small interfering RNA (siRNA) or a CXCR4 antagonist (AMD3100).Conclusion:5-FU possesses a pro-pigmentary activity through activation of the CXCL12/CXCR4 axis to drive the chemotactic migration of melanocytes.

The Promising Role of Chemokines in Vitiligo: From Oxidative Stress to the Autoimmune Response

“…The increased levels of CXCL12 were observed during the wound healing of excisional or burn injuries, especially in wound margins, and the activation of the CXCL12/CXCR4 axis lead to the accumulation of eosinophil and accelerate the neovascularization and epithelialization [ 87 , 88 ]. A more recent study revealed that 5-fluorouracil (5-FU) significantly increased the CXCL12 level in the vitiligo skin, and blocking the CXCL12/CXCR4 pathway, in turn, inhibited melanocyte migration [ 89 ]. It is hypothesized that under proper injury, the CXCL12-enriched microenvironment may favor melanocyte recruitment by trafficking corresponding melanocyte precursors into the perilesional and lesional vitiligo areas to induce therapeutic effects.…”

A simple drug‐delivery microneedling technique modality successfully improves linear atrophic scars

“…2 It has been widely used as a safe and effective intralesional therapy to potentialize the effects of triamcinolone to treat keloids and hypertrophic scars, 7,9 and it also improves skin color in pigmentary disorders, such as guttate idiopatic hypomelanosis 8,10 and vitiligo, 10 possibly by stimulating the secretion of CXCL12 by dermal fibroblasts. 11 Microneedling improves scars due to stimulation of neocollagenesis, angiogenesis and by reorganizing fibrosis. 5-FU has been widely…”

Low CPEB1 levels may predict the benefit of 5-fluorouracil treatment in patients with colon or stomach adenocarcinoma

“…Although patient life expectancy can be significantly extended by 5-FU-based chemotherapy, drug resistance is a major barrier to the success of this treatment (19). Due to complex and heterogeneous biological processes, many of the mechanisms of chemoresistance remain elusive (20). Therefore, there is a need to identify novel biomarkers for patient selection to improve the efficacy of 5-FU.…”