Neurotensin receptor 1 antagonist SR48692 improves response to carboplatin by enhancing apoptosis and inhibiting drug efflux in ovarian cancer

Purpose: The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), is correlated with tumor cell aggressiveness in most solid tumors. As chemo-resistance and tumor aggressiveness are often related; we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer (OC).Experimental Design: Experimental tumors and in vitro studied were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692. We measured the effects of these treatments on cell apoptosis and apoptosis related proteins, platinum accumulation in the cell and nucleus, and the expression and localization of platinum transporters. NTS and NTSR1 labelling was measured in patients with ovarian cancer. Results: SR48692 enhanced the response to carboplatin in OC cells and experimental tumors. When SR48692 is combined to carboplatin, we noted a major improvement of platinum induced DNA damage and cell death, as well as a decrease in tumor growth. The relationship of these results to clinic studies was made by the detection of NTS and NTSR1 in 72% and 74% of OC, respectively. Furthermore, in a large series of high grade OC, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance. Conclusions: This study strongly suggests that the addition of NTSR1 inhibitor in combination with platinum salt-based therapy will improve the response to the drug.

http://ift.tt/2wGuHz8