Influence of Tacalcitol on Cell Cycle Kinetics of Human Keratinocytes following Standardized Injury

Abstract

In the last few years, tacalcitol (1α,24-dihydroxy vitamin D₃, TV-02) has become widely available for the topical treatment of psoriasis. Several studies documented its effect on epidermal differentiation, inflammation and proliferation. Especially the effect on epidermal proliferation has shown to be most substantial. This finding strongly suggests that the antipsoriatic effect of tacalcitol may be mediated by the normalization of epidermal cell cycle kinetics. Aim of the present study was to investigate the effect of tacalcitol ointment (4 µg/g) compared with the ointment base on epidermal proliferation following tape stripping. In particular, we addressed the question to what extent tacalcitol influences the recruitment of G₀ cells after standardized injury. In 15 healthy volunteers, Sellotape^TM stripping of the epidermis was performed at two places on the lower back. Then, tacalcitol ointment (4 µg/g) and the ointment base were applied on the lesions and covered by a semiocclusive dressing. Punch biopsies of the lesions were obtained at 24, 32, 38, 44, 50, and 56 h after tape stripping. Using a flow cytometric staining procedure with parameters for epidermal proliferation (DNA content), differentiation (keratin 10 expression) and nonmesenchymal cells (vimentin expression), quantitative data were obtained. There was a statistically significant difference between the time intervals for tacalcitol and placebo with respect to the percentage of recruited basal cells in S phase: The peak of recruited basal cells in S phase was seen at 38 h for the placebo-treated lesions, whereas this peak was seen at 50 h for the tacalcitol-treated lesions. There was no significant difference in the total number of recruited cells between tacalcitol and placebo. The influence of tacalcitol on epidermal keratinization and on the percentage of nonkeratinocytes did not show any significance compared to placebo. We concluded that the mode of action of tacalcitol on proliferation is mainly through an extension of the cell cycle time of keratinocytes and/or an extension of the duration of the recruitment process of cycling cells, whereas the ability to suppress recruitment of resting keratinocytes is not different from placebo. Moreover, because of the limited effect of tacalcitol on epidermal keratinization, combination treatments with agents which interfere with keratinization and/or inflammation may be attractive.

Monitoring hyperproliferative disorders in human skin: Flow cytometry of changing cytokeratin expression

“…They observed a significant increase in all parameters for cell proliferation and a three-to fivefold increase in the percentage of cells in the S/G 2 /M phase of the cell cycle. This is in line with our findings; in fact, we found an even more dramatic increase of up to 30% at 48 h after tape stripping, which is in keeping with several studies from our group (16,19,20). This proliferative response is believed to be the result of the recruitment of cells from the G 0 pool into the cycling phase (21).…”

Calcitriol and Its Analogs Establish the Immunosuppressive Microenvironment That Drives Metastasis in 4T1 Mouse Mammary Gland Cancer

“…One of such compounds synthesized is the vitamin D 3 metabolite, (24 R )-1,24-dihydroxyvitamin D 3 (tacalcitol, 1,24(OH) 2 D 3 , PRI-2191). It is well documented that PRI-2191 inhibits cancer cell proliferation by inducing the differentiation of epidermal mouse and human keratinocytes in the case of psoriasis, and leukemic cells in the case of acute myeloid leukemia [ 24 , 25 ]. PRI-2191 also binds to the VDR with an affinity greater than or similar to that of calcitriol, but shows weaker induction of calcemia than that of calcitriol [ 20 , 26 ].…”

Vitamin D and the Skin

“…1 α, 25‐(OH) 2 D 3 clearly suppressed the growth of keratinocytes at concentrations higher than 10 −8 M. This growth suppression was effected by inhibition of DNA synthesis, as demonstrated by 3 H‐thymidine and BrdU incorporation studies. It is due to blockage at G1/S in the cell cycle, as shown in vitro and in vivo human keratinocytes (20, 21). At the same time, 1 α, 25‐(OH) 2 D 3 stimulated differentiation.…”