Renaissance of the biologically active vitamin A derivatives: Established and novel directed therapies for cancer and chemoprevention

Vitamin A and its biologically active derivatives are involved in a complex arrangements of physiological and developmental responses in many tissue of higher vertebrates. Retinoids are natural and synthetic compounds related to retinoic acid that act through interaction with two basic types of nuclear receptors: retinoic acid receptors (RAR alpha, RARbeta and RARgamma) and retinoid X receptors (RXRalpha, RXRbeta and RXRgamma) as retinoid-inducible transcription factors. Thus, the retinoid receptors are considered to be ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. They exert both beneficial and detrimental activity; they have tumor-suppressive activity but on the other hand they are teratogenic. Retinoids inhibit carcinogenesis, suppress premalignant epithelial lesions and tumor growth and invasion in a variety of tissues. Natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects. They are known to cause redifferentiation or to prevent further dedifferentiation of various neoplastic tissues. A number of novel chemical compounds, receptor selective retinoids and rexinoids, have been synthesized up to now and tested both in vitro and in vivo, using animal models against different cancer cells. In spite of that progress, there is still an urgent call for novel synthetic retinoids and rexinoids with greater retinoid receptor selectivity, reasonable chemotherapeutic or chemopreventive effects and reduced toxicity and side effects. This article summarizes selected effects of biologically active natural or synthetic retinoids and rexinoids, acting through their cognate nuclear receptors, and their use in chemotherapy and chemoprevention of various types of cancer.