Journal Article

Retinoids in chemoprevention and differentiation therapy

Laura A. Hansen, Caroline C. Sigman, Fausto Andreola, Sharon A. Ross, Gary J. Kelloff and Luigi M. De Luca

in Carcinogenesis

Volume 21, issue 7, pages 1271-1279
Published in print July 2000 | ISSN: 0143-3334
Published online July 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.7.1271
Retinoids in chemoprevention and differentiation therapy

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Retinoids are essential for the maintenance of epithelial differentiation. As such, they play a fundamental role in chemoprevention of epithelial carcinogenesis and in differentiation therapy. Physiological retinoic acid is obtained through two oxidation steps from dietary retinol, i.e. retinol→retinal→retinoic acid. The latter retinal→retinoic acid step is irreversible and eventually marks disposal of this essential nutrient, through cytochrome P450-dependent oxidative steps. Mutant mice deficient in aryl hydrocarbon receptor (AHR) accumulate retinyl palmitate, retinol and retinoic acid. This suggests a direct connection between the AHR and retinoid homeostasis. Retinoids control gene expression through the nuclear retinoic acid receptors (RARs) α, β and γ and 9-cis-retinoic acid receptors α, β and γ, which bind with high affinity the natural ligands all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoids are effective chemopreventive agents against skin, head and neck, breast, liver and other forms of cancer. Differentiation therapy of acute promyelocytic leukemia (APL) is based on the ability of retinoic acid to induce differentiation of leukemic promyelocytes. Patients with relapsed, retinoid-resistant APL are now being treated with arsenic oxide, which results in apoptosis of the leukemic cells. Interestingly, induction of differentiation in promyelocytes and consequent remission of APL following retinoid therapy depends on expression of a chimeric PML–RARα fusion protein resulting from a t(15;17) chromosomal translocation. This protein functions as a dominant negative against the function of both PML and RARs and its overexpression is able to recreate the phenotypes of the disease in transgenic mice. The development of new, more effective and less toxic retinoids, alone or in combination with other drugs, may provide additional avenues for cancer chemoprevention and differentiation therapy.

Keywords: AHR, aryl hydrocarbon receptor; APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; BCC, basal cell carcinoma; CBP, CREB-binding protein; CRABP, cellular retinoic acid-binding proteins; CRBP, cellular retinol-binding proteins; CYP, cytochrome P450; DMBA, 7,12-dimethylbenzanthracene; 4-HPR, N-(4-hydroxyphenyl)retinamide; NB, nuclear bodies; NMU, N-nitroso-N-methylurea; PML, promyelocytic leukemia protein; RA, retinoic acid; RAR, retinoic acid receptor; RAREs, retinoic acid response elements; RBP, retinol-binding protein; RXR, 9-cis-retinoic acid receptor; SCC, squamous cell carcinoma; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Journal Article.  8815 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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