A Ligand of Retinoid X Receptor Overcome Multidrug Resistance in Human Colon Carcinoma LoVomdr Cell Line

Multidrug resistance (MDR) is one of the major causes of failure of tumoral chemotherapy and it is often present in colorectal cancer. Some retinoids may have antitumoral effects also in MDR cancer cell lines. We investigated the anticancer effect of the all-trans retinoic acid (RA) and the 6-OH-11-O-hydroxyphenantrene (IIF), a specific ligand of Retinoid X Receptor (RXR), on a colon carcinoma doxorubicin resistant cell line (LoVoMDR). IIF and RA treatment inhibited proliferation and vitality and induced apoptosis in a time and dose dependent manner. Interestingly, IIF was significantly more effective than RA and in particular, IIF increased Bax and decreased Bcl-2 protein expression, as well as it inducer caspase-9, caspase-3 and PARP-1 cleavage after 24 hours of exposure. Furthermore, we studied the effects of these retinoids on two plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein-1 (MRP-1) and P-glycoprotein (P-gp). Expression and activity of P-gp, but not of MRP-1, was decreased by retinoids. Matrix Metalloproteinases (MMPs) -2 and -9, involved in cell invasion and metastasis, and Extracellular Matrix Metalloproteinase Inducer (EMMPRIN), a glycoprotein able to activate MMPs, were significantly reduced after IIF treatment. In conclusion we can suggest that IIF could be used to overcome MDR in human colon carcinoma and it may be a powerful tool in the development of cancer therapies.