Epithelial cells, retinoid effects

Retinoids, which are highly effective in the treatment of acne, stimulate epithelial cell turnover and aid in unclogging blocked pores. Retinoids also exhibit anti-inflammatory properties through the inhibition of neutrophil and monocyte chemotaxis.8 Because of these comedolytic and antiinflammatory effects, topical retinoids are recommended as first-line treatment for mild to moderate comedonal and inflammatory acne.3 While success is seen with monotherapy, using a retinoid in combination with benzoyl peroxide or topical antibacterials is also an appropriate and effective therapeutic treatment option.3 Tretinoin, adapalene, and tazarotene are topical retinoids available for use in the treatment of acne. Table 62-2 describes the strengths and formulations of these agents. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Agarwal C, Chandraratna RA, Johnson AT, Rorke EA, and Eckert RL [1996] AGN193109 is a highly effective antagonist of retinoid action in human ectocervical epithelial cells. J Biol Chem 271 12209-12212... 

Mechanism of Action A retinoid that decreases cohesiveness of follicular epithelial cells. Increases turnover of follicular epithelial cells. Bacterial skin counts are not altered. Transdermal Exerts its effects on growth and differentiation of epithelial cells. Antineoplastic Induces maturation, decreases proliferation of acute promyelocytic leukemia (APL) cells. Therapeutic Effect Causes expulsion of blackheads alleviates fine wrinkles, hyperpigmentation causes repopulation of bone marrow and blood by normal hematopoietic cells. 

H]Retinoic acid-treated human tracheobronchial epithelial cells contained several polar retinoic acid metabolites that coeluted with 4-oxo-, 4-hydroxy-, and 18-hydroxy-retinoic acid (Kim et al. 2000). 4-Hydroxy-retinoic acid could effectively induce MUC2 and MUC5AC mRNA expression in human tracheobronchial epithelial cells, indicating that it is an active retinoid able to induce mucous cell differentiation. 

In this section we first discuss the effects of retinoids on nonneoplastic cells in culture and then the effects of retinoids on cultured neoplastic cells. As discussed earlier, the cell types affected are not limited to epithelial cells but include also cells of mesenchymal origin and cells derived from neural ectoderm. Since most of these cell culture systems require serum, they inherently include retinoids. However, it is not known whether all of these cell types have a requirement for retinoids. Therefore, one should always attempt to relate studies of retinoid action in vitro to the function of those particular cell types in vivo. 

Retinoids have been shown to exert effects on differentiation of both epithelial cells (keratinocytes) and mesenchymal cells (chondrocytes, adipocytes, and hematopoetic cells) in eulture, much as had been observed both in vivo (Wolbach and Howe, 1925) and in organ culture in vitro (see previous section). In certain other cells, only growth and not differentiation is affected. Whether both types of effects have a common basis will have to await mechanistic studies. 

Seewald VL, Kim JH, Caldwell LE, Johnson BS, Swisshelm K, Collins SJ (1997) All-trans reiinoic acid mediates G1 arrest but not apoptosis in normal human mammary epithelial cells. Cell Growth Differ 8 631-641 Wilcken NRC, Scarcenc B, Musgrove EA, Sutherland RL (1996) Differential effects of retinoids and anti-... 

Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity. Retinoids have many important functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation, and bone growth, immune defense, and tumor suppression. Because vitamin A affects normal epithelial differentiation, it was investigated as a treatment for cutaneous disorders but was abandoned initially because of unfavorable side effects. Molecular modifications yielded compounds with vastly improved margins of safety. 

Other in vitro experiments utilizing a wide variety of cell lines, both epithelial and fibroblastic, both nonneoplastic and neoplastic, have both supported and amplified these earlier observations. To simplify the presentation of the complex effects of retinoids on glycoprotein synthesis, various experimental systems have been listed in Table I, A. Only general features common to these investigations are discussed here. 

The experiments of Lotan et al. (1982a) showed decreases in the poly(A)+RNA population of S91 melanoma cells cultured for 5 days in the presence of 10 retinoic acid as compared to controls. Such treatment results in nearly 90% inhibition of the growth of the cells. Protein synthesis by these cells was depressed relative to control cultures, as evidenced not only by the decreased poly(A) + RNA levels but also by decreases in the proportions of ribosomes in polysomes and decreases in polysome-associated mRNA. In contrast to the effects of Omori and Chytil (1982) on a differentiating epithelial tissue, Lotan et al. (1982a) found little qualitative differences in the protein patterns of treated or control cells. Further experiments should help answer the question of whether the underlying mechanisms of retinoid control of growth and differentiation are distinct or identical. 

---