Retinoids and their biological effects against cancer (original) (raw)
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Retinoids as Critical Modulators of Immune Functions: New Therapeutic Perspectives for Old Compounds
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2009
Retinoids are vitamin A derivatives that critically regulate several physiological and pathological processes, including immune functions and cancer development. These biological response modifiers exhert their pleiotropic effects through the interaction with nuclear receptors, defined as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These ligand-activated nuclear receptors induce the transcription of target genes by binding to responsive elements in the promoter regions. RARs and RXRs are also capable to interact with other nuclear receptors, thus expanding their spectrum of action on gene expression. Evidence has been accumulated indicating that retinoids may exert beneficial effects in both immune-mediated disorders and tumors.
Retinol (vitamin A) is a cofactor in CD3-induced human T-lymphocyte activation
Immunology, 1997
Immunomodulatory effects of different retinoids have been demonstrated, both in vivo and in vitro, in different cellular lineages including human and murine thymocytes, human lung fibroblasts, Langerhans' cells, tumoral cells and natural killer (NK) cells; however, any attempt to demonstrate the effect of retinoids on human peripheral blood mononuclear cells (PBMC) resulted in negative results. In the present work, it is shown that retinol and retinoic acid induce a marked increase of proliferation on human PBMC from 32 unrelated healthy individuals, which had previously been stimulated with anti-CD3 antibodies 48 hr before. Serum-free medium, specific retinoid concentration (10-' M) and a particular timing of retinol addition to the cultures (48 hr after CD3 stimulation) was necessary clearly to detect this retinol-enhancing effect. The increased proliferative response is specifically mediated via the clonotipic T-cell receptor-CD3 complex and correlates with the up-regulation of certain adhesion/activation markers on the T-lymphocyte surface: CD18, CD45RO and CD25; also Thl-type of cytokines (interleukin-2 and interferon-y) are found concordantly increased after retinoid costimulation, both measured by a direct protein measurement and by a specific mRNA increase. In addition, it is shown that the in vitro retinol costimulation is only present in immunodeficient patients who have no defect on CD3 molecules and activation pathway. The fact that retinol costimulate lymphocytes only via CD3 (and not via CD2 or CD28) and the lack of response enhancement in immunodeficients with impaired CD3 activation pathway indicates that retinoids may be used as therapeutic agents in immune system deficiencies that do not affect the clonotypic T-cell receptor.
Retinoic acid and cancer treatment
Retinoic acid which belongs to the retinoid class of chemical compounds is an important metabolite of vitamin A in diets. It is currently understood that retinoic acid plays important roles in cell development and differentiation as well as cancer treatment. Lung, prostate, breast, ovarian, bladder, oral, and skin cancers have been demonstrated to be suppressed by retinoic acid. Our results also show that low doses and high doses of retinoic acid may respectively cause cell cycle arrest and apoptosis of cancer cells. Also, the common cell cycle inhibiting protein, p27, and the new cell cycle regulator, Cdk5, are involved in retinoic acid's effects. These results provide new evidence indicating that the molecular mechanisms of/in retinoic acid may control cancer cells' fates. Since high doses of retinoic acid may lead to cytotoxicity, it is probably best utilized as a potential supplement in one's daily diet to prevent or suppress cancer progression. In this review, we have collected numerous references demonstrating the findings of retinoic acid in melanoma, hepatoma, lung cancer, breast cancer, and prostate cancer. We hope these observations will shed light on the future investigation of retinoic acid in cancer prevention and therapy.
Cancer, 1980
The effects of various retinoids on the proliferative capacities and on the synthesis of DNA, RNA, and protein have been investigated in MCF-7 mammary carcinoma cells in culture. Of the various retinoids tested, retinoic acid revealed maximum activity in inhibiting cell proliferation and thymidine incorporation. The degree of inhibition of cell proliferation by the various retinoids paralleled their capacity to inhibit thymidine incorporation, suggesting suppression of DNA synthesis as a primary cause of restriction of cell growth by these compounds. Two nonepithelial human cell lines were tested for sensitivity to retinoids, and showed diminished responses compared with MCF-7 cells. This suggests a correlation between the ability of retinoids to exert control of differentiation and cell proliferation for a given cell type. Reversibility of the effect of retinoid treatment, high cell viability, and lack of retinoidinduced lysosomal enzyme release, as shown in our studies, indicate that cytotoxicity may be excluded as a cause of decreased cell proliferation and inhibition of thymidine incorporation by retinoids. Cancer 46:2203-2209, 1980. ETINOIDS ARE KNOWN to regulate the differ-R entiation of normal epithelial tissue.'.""."' There have been numerous studies of the prophylactic effects of retinoids on epithelial tumors such as chemically induced tumors of mammary glands,12 skin,' urinary bladder,:'2 and prostate. l 5 Retinoids have also been shown to enhance the antitumor effects of x-rays and chemotherapeutic agents.'.".' The effects of retinoids on cultured tumor cells have been investigated. Dion et u/.$I showed that retinoic acid restored density-dependent inhibition of growth in mouse L-929 cells. Various investigators have examined the inhibitory effects of retinoic acid and retinyl acetate on untransformed and transformed cells in
Retinoids: novel immunomodulators and tumour-suppressive agents?
British Journal of Pharmacology, 2012
Retinoids play important roles in the transcriptional activity of normal, degenerative and tumour cells. Retinoid analogues may be promising therapeutic agents for the treatment of immune disorders as different as type I diabetes and systemic lupus erythematosus. In addition, the use of retinoids in cancer treatment has progressed significantly in the last two decades; thus, numerous retinoid compounds have been synthesized and tested. In this paper, the actual or potential use of retinoids as immunomodulators or tumour-suppressive agents is discussed.