Retinoic acid differentiation

Ehrich et al. (1995) further determined NTE and AChE activities in SY5Y cells differentiated with retinoic acid or NGF after treatment with paraoxon, DFP, parathion, and inipafox. SY5Y cells differentiated with retinoic add show similar AChE and NTE inhibition by DFP, paraoxon, and parathion compared to cither undifferentiated or NGF-differcntiatcd cells. However, mipafox-induced inhibition is much lower in retinoic acid-differentiated cells. These findings suggest that SY5Y cells differentiated with NGF... 

In comparison with the polymeric colloidal carriers mentioned so far, SLN are much more compatible with phagocytic cells. SLN composed of different lipids and surfactants do not exert any cytotoxic effects up to concentrations of 2.5% lipid, and even concentrations up to 10% led to a viability of 80% with human granulocytes [20]. Similar results were obtained in retinoic acid-differentiated HL-60 cells, whereas polymethylcyanoacrylate and polyhexylcyanoacrylate nanoparticles at concentrations of 0.05% or 0.35% led to complete cell death. In this chapter, the results of cytotoxicity testing of SLN on freshly isolated peritoneal mouse macrophages are presented. 

Tretinoin, the - -trans isomer of retinoic acid [302-79-4] was shown in the 1960s to be useful for the treatment of disorders associated with abnormal epithehal differentiation. 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Included among other differentiating cell lines which have been established in culture, is the human promyelocytic cell line HL-60, which differentiates into more mature myeloid cells upon treatment with retinoic acid and prostaglandin E] (PGEi). Friend erythroleukemia cells differentiate into hemoglobin-producing cells when treated with either dimethyl sulfoxide, or hexamethylene bis-acetamide. 

Retinoic Acid Has a Role in the Regulation of Gene Expression Tissue Differentiation... 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Vitamin A is essential throughout life, including foetal development, but perhaps its most well researched role is that in vision where 11 -cis retinaldehyde is the initial part of the photoreceptor complex in rods and cones. Retinoic acid induces differentiation in epithelial cells and deficiency leads to... 

Vitamin A (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

Villiger PM, Terkeltaub R, Lotz M. Monocyte chemoattractant protein-1 (MCP-1) expression in human articular cartilage. Induction by peptide regulatory factors and differential effects of dexamethasone and retinoic acid. J Clin Invest 1992 90(2) 488 196. 

Simeone, A., Acampora, D., Nigro, U., Faiella, A., D Esposito, M., Stomaiuolo, A., Mavilio, F., and Boncinelli, E. (1991). Differential regulation by retinoic acid of the homeobox genes of the four HOX loci in human embryonal carcinoma cells. Mech. Dev. 33 215-228. 

Sumantran, VN, Zhang, R, Lee, DS, and Wicha, MS, 2000. Differential regulation of apoptosis in normal versus transformed mammary epithelium by lutein and retinoic acid. Cancer Epidemiol Biomarkers Prev 9, 257-263. 

Liu, Y., Chang, R.L., Cui, X.X., Newmark, H.L. and Conney, A.H. 1997. Synergistic effects of curcumin on all-trans retinoic acid- and 1 alpha,25-dihydroxyvitamin D3-induced differentiation in human promyelocytic leukemia HL-60 cells. Oncol Res 9 19-29. 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

Granulocyte differentiation acute promyelocytic leukemia PBMCs (in vivo) Cultured bone marrow mononuclear cells (in vitro) All-trans retinoic acid (ATRA) Promoter analysis of ATRA response genes suggest molecular mechanism underlying ATRA-induced granulocytic differentiation [30]... 

Histochemical studies of bone marrow samples show that peroxidase-containing granules are detectable in promyelocytes. The human promyelo-cytic leukaemia cell line HL-60 grows easily in culture, and the cells resemble promyelocytes both structurally and functionally. Furthermore, they can be induced to differentiate in vitro upon addition of various agents, such as retinoic acid and phorbol esters, and these differentiated cells resemble more mature forms of neutrophils. HL-60 cells possess almost the same amount of myeloperoxidase (4.4 fig per 106 cells) as mature neutrophils, and the enzyme purified from these cells has the same subunit structure. The cells thus actively synthesise the enzyme only until they are induced to differentiate. This cell line has been extensively used to study the molecular events controlling the expression of enzymes such as myeloperoxidase, and also to investigate the molecular controls that lead to a cessation of their expression. 

Agarwal C, Chandraratna RAS, Teng M, Nagpal S, Rorke EA, and Eckert RL [1996] Differential regulation of human ectocervical epithelial cell line proliferation and differentiation by retinoid x receptor- and retinoic acid receptor-specific retinoids. Cell Growth Differentiation 7 521-530... 

Baltes S, Nau H, and Lampen A [2004] All-trans retinoic acid enhances differentiation and influences permeability of intestinal Caco-2 cells under serum-free conditions. Dev Growth Differentiation 46 503-514... 

Kawasaki H, Eckner R, Yao TP, Taira K, Chiu R, Livingston DM, Yokoyama KK (1998) Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation. Nature 393(6682) 284-289... 

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