Retinoids in chemoprevention and differentiation therapy

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

Research output: Contribution to journalReview article

242 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1271-1279
Number of pages9
JournalCarcinogenesis
Volume21
Issue number7
DOIs
StatePublished - Jan 1 2000

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Hansen, L. A., Sigman, C. C., Andreola, F., Ross, S. A., Kelloff, G. J., & De Luca, L. M. (2000). Retinoids in chemoprevention and differentiation therapy. Carcinogenesis, 21(7), 1271-1279. https://doi.org/10.1093/carcin/21.5.271