ANTITUMORAL EFFECT OF RETINOIDS: A COMPARISON BETWEEN ALL TRANS RETINOIC ACID AND IIF, A SPECIFIC LIGAND OF RXR

Several studies suggest the employment of retinoids in the therapy of cancer. These molecules, that are natural derivatives of vitamin A or retinol and include the all-trans-retinoic acid (RA), play important roles in modulating normal or tumor cell growth through the regulation of differentiation and/or apoptosis. The clinical use of retinoids is complicated by the fact that the doses needed for successful treatment are often toxic, leading to hypervitaminosis A syndrome; another major problem is that in some patients cancer cells become resistant to these compounds. The retinoid signal is mediated in target cells through specific nuclear receptors: the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). RARs and RXRs are divergent in their ligand specificity; RA can bind and activate only RAR receptors, by contrast, 9-cis- retinoic acid binds RARs and RXRs, but with different affinities. It has been demonstrated that the retinoids that are ligands of RXR are e

Growth Inhibition and Proapoptotic Activity Induction by IIF and Valproic Acid on RA-resistant Leukemia Cells.

All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukaemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. In an attemp to mimic clinical conditions for the treatment of leukemia, a stably RA-resistant subclone of the human promyelocytic leukemia cell line HL60 (HL60-R) was developed to study the antiproliferative and proapoptotic effect of the retinoid IIF (6-OH-11-O-hydroxyphenantrene) in comparison with RA. Moreover wheter the inhibitor of histone deacetylase (HDAC) activity, valproic acid (VPA), could enhance sensitivity to retinoids in HL60-R cells was evaluated. Finally, the effect of IIF on the expression of multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp) was evaluated. It was found that IIF strongly suppressed cell proliferation (as measured by growth curves) and induced apoptosis (as measured by DNA fragmentation and Annexin V detection assay), while RA was practically ineffective. The addition of VPA to IIF accentuated the antiproliferative effect of IIF alone and increased apoptosis; the combination of VPA with RA allowed growth arrest. Moreover IIF caused a reduction of transmembrane transporter expression, particularly of P-gp, as shown by Western blotting. Our results suggest that IIF may be useful in controlling the proliferation of RA-resistant leukemia cells, especially in combination with an HDAC inhibitor such as VP