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• W2053821347 abstract "Nelson et al. confirmed the previously described antiproliferative effect of isotretinoin on human sebocytes. They attributed a portion of this decrease to cell cycle arrest and detected sebocyte apoptosis, which was not recapitulated by alitretinoin or tretinoin. These events were specific to sebocytes, as isotretinoin failed to induce apoptosis in keratinocytes. Isotretinoin-induced apoptosis was shown to be an RAR-independent mechanism. Nelson et al. confirmed the previously described antiproliferative effect of isotretinoin on human sebocytes. They attributed a portion of this decrease to cell cycle arrest and detected sebocyte apoptosis, which was not recapitulated by alitretinoin or tretinoin. These events were specific to sebocytes, as isotretinoin failed to induce apoptosis in keratinocytes. Isotretinoin-induced apoptosis was shown to be an RAR-independent mechanism. Isotretinoin (13-cis retinoic acid), the compound that has revolutionized the treatment of severe acne for over 25 years, is most effective in reducing sebaceous gland size by decreasing proliferation of basal sebocytes, in suppressing sebum production up to 90% by inhibiting sebaceous lipid synthesis, and in prohibiting the progression of sebocyte differentiation in vivo and in vitro (Zouboulis and Orfanos, 2000Zouboulis C.C. Orfanos C.E. Retinoids.in: Millikan L.E. Drug Therapy in Dermatology. Marcel Dekker, New York/Basel2000: 171-233Google Scholar). Despite its undeniable efficacy on acne and seborrhea, the molecular basis for the unique sebostatic activity of this compound is still not clearly understood. It may be the superb, tailored effect of isotretinoin on acne and its quick release for clinical use that have hindered interest in further basic research on it. Because retinoids exert most of their effects by modulating gene expression after binding to and/or activating nuclear retinoid receptors, the strong sebostatic activity of isotretinoin is particularly surprising, as it exhibits low binding affinities for both cellular retinoic acid-binding proteins (CRABPs) I and II as well as for nuclear retinoid receptors, retinoic acid receptors (RARs), and retinoid X receptors (RXRs) (Siegenthaler and Saurat, 1989Siegenthaler G. Saurat J.-H. Binding of isotretinoin to cellular retinoic acid-binding protein: a reappraisal.in: Marks R. Plewig G. Acne and Related Disorders. Dunitz, London1989: 169-177Google Scholar). In contrast, its stereoisomers tretinoin (all-trans retinoic acid) specifically binds to CRABPs and RAR and alitretinoin (9-cis retinoic acid) to RXR. Tsukada et al., 2000Tsukada M. Schröder M. Roos T.C. Chandraratna R.A.S. Reichert U. Merk H.F. et al.13-cis Retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors.J Invest Dermatol. 2000; 115: 321-327Crossref PubMed Scopus (163) Google Scholar have partially elucidated this apparent contradiction by showing that isotretinoin undergoes significant and selective isomerization to tretinoin in cultured sebocytes. Intracellular tretinoin acts via RAR to exert its antiproliferative effect on these cells. Isotretinoin has, therefore, been considered as a prodrug (Sitzmann et al., 1995Sitzmann J.H. Bauer F.W. Cunliffe W.J. Holland D.B. Lemotte P.K. In situ hybridization analysis of CRABP II expression in sebaceous follicles from 13-cis retinoic acid-treated acne patients.Br J Dermatol. 1995; 133: 241-248Crossref PubMed Scopus (25) Google Scholar; Tsukada et al., 2000), which exhibits its activity through isomerization to tretinoin (Tsukada et al., 2000) or metabolism to 4-oxo-isotretinoin or 4-hydroxy-isotretinoin (Zouboulis and Orfanos, 2000Zouboulis C.C. Orfanos C.E. Retinoids.in: Millikan L.E. Drug Therapy in Dermatology. Marcel Dekker, New York/Basel2000: 171-233Google Scholar. The 4-oxo metabolites of retinoids have been shown to be functionally active in human keratinocytes and fibroblasts by their ability to induce changes in gene expression (Baron et al., 2005Baron J.M. Heise R. Blaner W.S. Neis M. Joussen S. Dreuw A. et al.Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro.J Invest Dermatol. 2005; 125: 143-153Crossref PubMed Scopus (52) Google Scholar. Alternatively, isotretinoin has been suggested to act in a receptor-independent manner by influencing cellular signaling pathways through direct protein interactions as demonstrated with other retinoids or by enzyme inhibition (Imam et al., 2001Imam A. Hoyos B. Swenson C. Levi E. Chua R. Viriya E. et al.Retinoids as ligands and coactivators of protein kinase C alpha.FASEB J. 2001; 15: 28-30Crossref PubMed Scopus (68) Google Scholar; Karlsson et al., 2003Karlsson T. Vahlquist A. Kedishvili N. Törmä H. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?.Biochem Biophys Res Commun. 2003; 303: 273-278Crossref PubMed Scopus (49) Google Scholar. Several studies have indicated that the effects of retinoids on cell proliferation, cell cycle, and apoptosis are retinoid-specific or cell type-specific events. Isotretinoin has been found to be superior to other non-aromatic retinoids, such as tretinoin and alitretinoin, in reducing sebocyte proliferation and suppressing sebum production, whereas most aromatic retinoids do not reduce sebum synthesis (Zouboulis and Orfanos, 2000Zouboulis C.C. Orfanos C.E. Retinoids.in: Millikan L.E. Drug Therapy in Dermatology. Marcel Dekker, New York/Basel2000: 171-233Google Scholar). This superior effect of isotretinoin has been attributed to the delayed initiation of retinoid inactivation under incubation of sebocytes with isotretinoin, a fact that leads to high intracellular tretinoin concentrations. In contrast, incubation with tretinoin leads to rapid enhancement of CRABP-II expression, which reduces the free intracellular concentration of tretinoin through promotion of its metabolism by cytochrome P450 enzymes, and to induction of CYP1A1 expression, a major xenobiotic metabolizing enzyme, in cultured sebocytes (Tsukada et al., 2000). The antiproliferative activity of retinoids on human sebocytes and rat preputial sebocyte-like cells in vitro was found to be mediated by RAR (Tsukada et al., 2000; Kim et al., 2000Kim M.J. Ciletti N. Michel S. Reichert U. Rosenfield R.L. The role of specific retinoid receptors in sebocyte growth and differentiation in culture.J Invest Dermatol. 2000; 114: 349-353Crossref PubMed Scopus (43) Google Scholar). Human sebocytes have been shown to be naturally eliminated by apoptosis on their way to terminal differentiation before their death and holocrine secretion (Wróbel et al., 2003Wróbel A. Seltmann H. Fimmel S. Müller-Decker K. Tsukada M. Bogdanoff B. et al.Differentiation and apoptosis in human immortalized sebocytes.J Invest Dermatol. 2003; 120: 175-181Crossref PubMed Scopus (110) Google Scholar). Terminal differentiation and apoptosis are different genetically programmed cell events, both followed by cell death as an essential feature of eukaryotic cell life. Terminal differentiation of human sebocytes is associated with lipid synthesis, accumulation of lipid droplets in the cytoplasm, and increase of cell volume. Apoptotic events occur in parallel, as signs of nuclear degeneration followed by cell bursting and death. Sebocyte apoptosis in vitro can be enhanced in association with increased rates of terminal differentiation (Wróbel et al., 2003Wróbel A. Seltmann H. Fimmel S. Müller-Decker K. Tsukada M. Bogdanoff B. et al.Differentiation and apoptosis in human immortalized sebocytes.J Invest Dermatol. 2003; 120: 175-181Crossref PubMed Scopus (110) Google Scholar). Among other mechanisms, apoptosis has also been attributed to RXR nuclear receptor ligands through reduction of casein kinase 1α (Zhao et al., 2004Zhao Y. Qin S. Atangan L.I. Molina Y. Okawa Y. Arpawong H.T. et al.Casein kinase 1α interacts with retinoid X receptor and interferes with agonist-induced apoptosis.J Biol Chem. 2004; 279: 30844-30849Crossref PubMed Scopus (30) Google Scholar). Although increased levels of caspase 3 were noted in SZ95 sebocytes 24 hours after treatment with isotretinoin and inhibition of cell growth was evident at 7 days, other markers failed to provide evidence that SZ95 sebocytes were undergoing apoptosis at 24 hours in a previous report (Wróbel et al., 2003Wróbel A. Seltmann H. Fimmel S. Müller-Decker K. Tsukada M. Bogdanoff B. et al.Differentiation and apoptosis in human immortalized sebocytes.J Invest Dermatol. 2003; 120: 175-181Crossref PubMed Scopus (110) Google Scholar). Fenretinide, another non-aromatic retinoid, induces apoptosis by elevating reactive oxygen species and increases inactivation of ceramide and caspases (Wu et al., 2001Wu J.M. DiPietrantonio A.M. Hsieh T.C. Mechanism of fenretinide (4-HPR)-induced cell death.Apoptosis. 2001; 6: 377-388Crossref PubMed Scopus (107) Google Scholar). In addition, a retinoid-related molecule, AGN 193198, induces apoptosis without activation of the classical retinoid receptors (Balasubramanian et al., 2005Balasubramanian S. Chandraratna R.A. Eckert R.L. A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis.Oncogene. 2005; 24: 4257-4270Crossref PubMed Scopus (14) Google Scholar). A marked decrease in wax esters, a slight decrease in squalene, and a relative increase in cholesterol level have been detected in skin surface lipids after treatment with isotretinoin (Zouboulis and Orfanos, 2000Zouboulis C.C. Orfanos C.E. Retinoids.in: Millikan L.E. Drug Therapy in Dermatology. Marcel Dekker, New York/Basel2000: 171-233Google Scholar). Oral isotretinoin was also shown to decrease the triglyceride fraction, whereas free sterols and total ceramides were found to be increased in comedonal lipids. The inhibitory effect of isotretinoin on sebaceous lipids has been attributed to inhibition of terminal sebocyte differentiation (Zouboulis et al., 1994Zouboulis C.C. Krieter A. Gollnick H. Mischke D. Orfanos C.E. Progressive differentiation of human sebocytes in vitro is characterized by increased cell size and altered antigenic expression and is regulated by culture duration and retinoids.Exp Dermatol. 1994; 3: 151-160Crossref PubMed Scopus (56) Google Scholar) and is probably mediated by both RAR and RXR (Tsukada et al., 2000; Kim et al., 2000Kim M.J. Ciletti N. Michel S. Reichert U. Rosenfield R.L. The role of specific retinoid receptors in sebocyte growth and differentiation in culture.J Invest Dermatol. 2000; 114: 349-353Crossref PubMed Scopus (43) Google Scholar). Moreover, isotretinoin has been shown to competitively inhibit the 3α-hydroxysteroid activity of retinol dehydrogenase, leading to decreased androgen synthesis in vitro (Karlsson et al., 2003Karlsson T. Vahlquist A. Kedishvili N. Törmä H. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?.Biochem Biophys Res Commun. 2003; 303: 273-278Crossref PubMed Scopus (49) Google Scholar). Like all retinoids, isotretinoin has also been shown to exert anti-inflammatory activity through an inhibition of the migration of polymorphonuclear leukocytes into the skin, supporting its role in the reduction of inflammation that is associated with acne (Wozel et al., 1991Wozel G. Chang A. Zultak M. Czarnetzki B.M. Happle R. Barth J. et al.The effect of topical retinoids on the leukotriene-B4-induced migration of polymorphonuclear leukocytes into human skin.Arch Dermatol Res. 1991; 283: 158-161Crossref PubMed Scopus (37) Google Scholar). Isotretinoin reduced the increased expression of pro-matrix metalloproteinase (MMP)-9 and MMP-13 in the sebum of acne patients and inhibited the arachidonic acid-induced secretion and mRNA expression of pro-MMP-2 and pro-MMP-9 in SZ95 sebocytes in vitro, indicating that the influence of isotretinoin on sebocyte inflammatory signaling is likely to be induced by MMP (Papakonstantinou et al., 2005Papakonstantinou E. Aletras A.J. Glass E. Tsogas P. Dionyssopoulos A. Adjaye J. et al.Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin.J Invest Dermatol. 2005; 125: 673-684Crossref PubMed Scopus (104) Google Scholar). The origin of MMP and tissue inhibitors of MMP in sebum has been attributed to keratinocytes and sebocytes. Nelson et al. (Nelson et al., 2006Nelson A.M. Gilliland K.L. Cong Z. Thiboutot D.M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.J Invest Dermatol. 2006; 126: 2178-2189Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, this issue) reexamine the effects of isotretinoin, alitretinoin, and tretinoin on cell proliferation, cell cycle proteins, and apoptosis of SEB-1 sebocytes and keratinocytes and confirm the previous reports concerning the dose- and time-dependent antiproliferative effect of isotretinoin on natural and immortalized SZ95 sebocytes (Zouboulis et al., 1991Zouboulis C.C. Korge B. Akamatsu H. Xia L. Schiller S. Gollnick H. et al.Effects of 13-cis-retinoic acid, all-trans-retinoic acid, and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro.J Invest Dermatol. 1991; 96: 792-797Abstract Full Text PDF PubMed Google Scholar; Zouboulis et al., 1999Zouboulis C.C. Seltmann H. Neitzel H. Orfanos C.E. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95).J Invest Dermatol. 1999; 113: 1011-1020Crossref PubMed Scopus (277) Google Scholar; Tsukada et al., 2000Tsukada M. Schröder M. Roos T.C. Chandraratna R.A.S. Reichert U. Merk H.F. et al.13-cis Retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors.J Invest Dermatol. 2000; 115: 321-327Crossref PubMed Scopus (163) Google Scholar). A portion of this decrease was attributed to an influence on the G1/S phase of the cell cycle, as evidenced by decreased DNA synthesis, increased p21 protein, and decreased cyclin D1 protein, and, therefore, to cell cycle arrest. Nelson et al., 2006Nelson A.M. Gilliland K.L. Cong Z. Thiboutot D.M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.J Invest Dermatol. 2006; 126: 2178-2189Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar also confirm that no isotretinoin-induced apoptosis is apparent within a 24-hour treatment period (Wróbel et al., 2003Wróbel A. Seltmann H. Fimmel S. Müller-Decker K. Tsukada M. Bogdanoff B. et al.Differentiation and apoptosis in human immortalized sebocytes.J Invest Dermatol. 2003; 120: 175-181Crossref PubMed Scopus (110) Google Scholar). By using annexin V–FITC staining, TUNEL staining, and cleaved caspase 3 protein analysis, Nelson et al., 2006Nelson A.M. Gilliland K.L. Cong Z. Thiboutot D.M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.J Invest Dermatol. 2006; 126: 2178-2189Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar were, however, able to detect a marginal induction of apoptosis in SEB-1 sebocytes by isotretinoin after 48 and 72 hours of treatment. The ability of isotretinoin to induce apoptosis was not recapitulated by alitretinoin or tretinoin. The induction of cell cycle arrest and apoptosis by isotretinoin was specific to sebocytes, as the compound failed to induce apoptosis in HaCaT keratinocytes or normal human epidermal keratinocytes. Furthermore, the RAR pan-antagonist AGN 193109 did not inhibit the apoptosis induced by isotretinoin; this suggests an RAR-independent apoptotic mechanism. The processes described by Nelson et al., 2006Nelson A.M. Gilliland K.L. Cong Z. Thiboutot D.M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.J Invest Dermatol. 2006; 126: 2178-2189Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, such as cell cycle arrest and apoptosis of sebocytes, provide an explanation for the histological data that demonstrated a drastic decrease in the size, shape, and lipid content of sebaceous glands in human skin under isotretinoin treatment (Landthaler et al., 1980Landthaler M. Kummermehr J. Wagner A. Plewig G. Inhibitory effects of 13-cis-retinoic acid on human sebaceous glands.Arch Dermatol Res. 1980; 269: 297-309Crossref PubMed Scopus (95) Google Scholar). Taken together, the existing data indicate that, in sebocytes, isotretinoin causes inhibition of cell proliferation after intracellular metabolism to tretinoin by an RAR-mediated pathway and cell cycle arrest and apoptosis by an RAR-independent mechanism, which contributes to its sebosuppressive effect (Table 1). Induction of cell cycle arrest and apoptosis by isotretinoin is likely to contribute to the overall effect on suppression of sebum, but isotretinoin also inhibits sebaceous lipid synthesis by an RAR- and RXR-mediated pathway. Finally, the anti-inflammatory effect of isotretinoin has been attributed to a reduction of MMP in sebum. The abi-lity of isotretinoin to induce apoptosis is specific to sebocytes, not to keratinocytes, and is distinct from effects observed with alitretinoin and tretinoin that may account, in part, for the superior efficacy of isotretinoin in reducing sebum production.Table 1Isotretinoin effectiveness on human sebocytesCellular functionEffectCellular mechanismMolecular mechanismProliferationASebocyte-specific.InhibitionIntracellular isomerization in tretinoinRAR-mediatedProliferation/ApoptosisASebocyte-specific.Inhibition/InductionCell cycle arrestRetinoid receptor-independentLipid synthesisASebocyte-specific.ReductionInhibition of terminal differentiationRAR- and RXR-mediatedLipid synthesisDecreased androgen synthesisInhibition of 3α hydroxysteroid activity of retinol dehydrogenaseInflammationInhibitionInhibition of the migration of neutrophilsReduction of MMP expressionA Sebocyte-specific. Open table in a new tab The processes described by Nelson et al. provide an explanation for the histological data that demonstrated a drastic decrease in the size, shape, and lipid content of sebaceous glands in human skin under isotretinoin treatment. The processes described by Nelson et al. provide an explanation for the histological data that demonstrated a drastic decrease in the size, shape, and lipid content of sebaceous glands in human skin under isotretinoin treatment. The author states no conflict of interest." @default.
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• W2053821347 title "Isotretinoin Revisited: Pluripotent Effects on Human Sebaceous Gland Cells" @default.
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