Retinoids, natural and synthetic signaling molecules that are structurally related to vitamin A. Compounds such as retinol, retinal, retinoic acid , retinyl esters and other derivatives are considered in the group of retinoids. Retinoids are considered the most important regulators of several essential biological functions. For example, an active derivative of retinol (vitamin A metabolite), such as retinoic acid (RP), plays a major role in vision, cell differentiation, tissue homeostasis, apoptosis, organogenesis , regulation of the immune system and the formation of embryonic patterns (1). Additionally, RA is also considered a potent chemopreventive and tumor suppressor agent due to its apoptotic and antioxidant activity. A wide variety of animal model studies and clinical trials have shown the anticancer activity of RA against different types of cancers such as lymphoma, leukemia, melanoma, lung cancer, cervical cancer. uterus, kidney cancer, neuroblastoma and glioblastoma (2). RA has also been shown to promote the generation of ROS, including free radicals, responsible for the expression of antioxidant enzymes in rat sertoli cells and human retinal pigment epithelial cells (3) (4) . Retinoids mediate their physiological effects via interaction with two distinct classes of nuclear receptors, including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These two nuclear receptors belong to members of the steroid and thyroid hormone receptor superfamily (5) (6). All-trans-retenenoic acid (ATRA) and 9-cis-retenenoic acid (9CRA) are the two isomers of RA that act as ligands and bind to the nuclear receptors RAR and RXR. Although it is well known that 9CRA only binds to RXRs, whereas as ligands ATRA and 9CRA...... middle of paper ...... diet deficient in tamine A (VAD) to determine the specific antagonistic activity of RA on Nrf2. Interestingly, experimental Western blot data of proteins in the small intestine of Nrf2 +/+ showed increased levels of Gstm5, GCLC, NQO1, and Gsta1/2, but not in Nrf2 −/ mice. -. Furthermore, administration of ATRA to Nrf2 +/+ mice on the VAD diet showed an almost complete blockade of the increase in Gstm5, GCLC, NQO1 and Gsta1/2 proteins in the small intestine. This ARE-induced repression of gene expression strongly suggests the antagonistic role of ATRA on Nrf2. Taken together, the above results suggest that targeting Nrf2 inhibition via RARα could become a new therapeutic approach to combat drug resistance in tumor cells. However, further structural studies on Nrf2:RARα interactions are needed to know which domain of RARα might react with Nrf.2.