Antiproliferative Effect of Vitamin A and D Analogues on Adult Human Keratinocytes in vitro

Abstract

Background: Vitamin A and D analogues play an important role in epidermal homeostasis and are used in the treatment of various skin diseases. The failure of retinoid and vitamin D treatments is sometimes difficult to explain. Methods: We analyzed the effect of all-trans retinoic acid (all-trans RA), 13-cis retinoic acid (13-cis RA), ergocalciferol and cholecalciferol in keratinocyte cultures established from adult donors, on the cell proliferation by means of [³H]thymidine incorporation and apoptosis after fluorescein diacetate/trypan blue staining. Results: All tested agents exerted a dose-dependent inhibition of keratinocyte proliferation in the concentration range of 1.25–5 µM. Based on IC₅₀ values, the antiproliferative efficiency was as follows: cholecalciferol > ergocalciferol = all-trans RA > 13-cis RA. The observed effect of cholecalciferol and ergocalciferol, but not retinoids, involved the induction of apoptotic cell death. Combining vitamins A and D did not further increase the proliferation block and even displayed an antagonistic effect. Conclusion: The susceptibility of keratinocytes to the antiproliferative action of vitamins A and D was markedly different in cell cultures derived from different donors, indicating a possible predictive value of the in vitro testing for the efficiency of the clinical response to these agents.

Vitamin D and Vitamin A Receptor Expression and the Proliferative Effects of Ligand Activation of These Receptors on the Development of Pancreatic Progenitor Cells Derived from Human Fetal Pancreas

“…CYP26 and CYP24 (19,32) were detectable in our PPC system; thus the usual down-regulatory systems for these vitamins appear to be absent in our PPC preparations. Whilst atRA and calcitriol can have antagonistic effects on each other [19,32] this seems unlikely to be the case in our PPC system since co-treatment with atRA and calcitriol had no such effects. Thus, the mechanisms for regulation of the effects of vitamin A and D in our PPCs require further investigation.…”

“…atRA and calcitriol act synergistically through RXR:VDR heterodimers to effect many of vitamin D's known effects; they also interact to inhibit the proliferation of breast (MCF-7) and ovarian cancer (NIH:OVCAR3) [30] and promote the differentiation of human promyeloid leukemia cells (HL-60) into monocytes [31]. The RAR and VDR can each heterodimerize with the retinoid X receptor (RXR), accounting for further interactions of the atRA and calcitriol signaling pathways [12,19,[32][33][34] and also of the cytochrome P450 superfamily enzymes CYP26 and CYP24 [12,19,35]. AtRA also down-regulates cellular levels of CYP24 while enhancing the actions of calcitriol [35].…”

Vitamina D – Perspetivas Atuais

“…Os 2 mecanismos principais são via VDR, que regula a expressão génica ao estimular a síntese de inibidores do ciclo celular como as proteínas p21 e p27, e por efeito não genómico que leva ao influxo de cálcio nas células alvo, o que estimula a sua diferenciação. [47][48][49][50] Os carcinomas espinocelulares e basocelulares apresentam em mais de 50% "assinatura UV", e in vitro a aplicação tópica de vitamina D parece acelerar a clearance dos dímeros de ciclobutano resultantes de lesão do DNA pela radiação UV. 51 Estudos in vitro e in vivo em modelos de carcinogénese cutânea em ratos têm mostrado que a vitamina D, por diversos mecanismos, teria um efeito supressor nas vias fisiopatológicas dos CEC e CBC.…”

The relationship of diet and acne

“…The susceptibility of keratinocytes to the antiproliferative effects of vitamins A and D has been reported. 27 It was documented that the observed inhibition of proliferation of mouse and human keratinocytes in vitro by retinoic acid is mediated by independent mechanisms to Peroxisome proliferator-activated receptors (PPAR) receptors an inconsistent notion that RA potentiates cell proliferation by activating PPARb/D. 28 Another report demonstrated that alltransRA, an isoform of RA, increased aquaporin 3 expression and enhanced its biological activity in human skin.…”