Abstract
The process of carcinogenesis involves genomic disasters that result in inactivation or underexpression of tumor/growth suppressor genes and/or overexpression of oncogenes. Decreased levels of tumor suppressors may result from DNA hypermethylation, mutations, translocation, or transcriptional repression. Therefore, logically, one of the most promising chemopreventive and chemotherapeutic targets appears to be the activation of tumor suppressors. The expression of tumor suppressor genes could be activated by reversal of epigenetic gene silencing by using DNA methyltransferase inhibitors and/or histone deacetylase inhibitors (Zelent et al, 2004). Alternatively, the expression of multiple tumor suppressor genes in cancer cells could be induced by ligand-dependent transcription factors, such as nuclear receptors for the active form of vitamin A, all-trans retinoic acid (ATRA) that belong to the superfamily of steroid/thyroid hormone nuclear receptors. Retinoids (ATRA and its synthetic analogs) exert their anti-proliferative and differentiation effects through retinoic acid receptors (RAR) that function as heterodimers with retinoid X receptors (RXR). RXR, a nuclear receptor for 9-cis retinoic acid, is an obligate partner of RAR in mediating retinoid action. Three distinct isotypes of RAR (, and ) and RXR (, and ) are encoded by separate genes. The RXR–RAR heterodimer binds to retinoic acid response elements (RARE) present in the promoter regions of responsive genes. RARE are direct repeat (DR) of 5'-RGKTCA-3' motifs (where R is A or G and K is G or T) separated by either two (DR-2) or five (DR-5) nucleotides (Nagpal and Chandraratna, 1998).
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