Reversal of P-glycoprotein-mediated multidrug resistance in human sarcoma MES-SA/Dx-5 cells by nonsteroidal anti-inflammatory drugs

Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is one of the major reasons for the failure of cancer therapy. Several chemosensitizers are able to reverse in vitro MDR by inhibiting P-gp, although high toxicity limits their clinical application. In this study, we aimed to investigate the in vitro effectiveness of four common nonsteroidal anti-inflammatory drugs (NSAIDs) such as Curcurnin (Cur), Sulindac (Sul), Ibuprofen (Ibu) and NS-398 (NS) to inhibit P-gp activity at clinically achievable doses and to evaluate their potential use as sensitizers in anti-cancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx-5) expressing high levels of P-gp, were treated with different doxo concentrations in the presence or absence of NSAIDs. Cellular accumulation of doxo, cytotoxicity and apoptosis induction were measured in comparison with Verapamil, a specific P-gp inhibitor, used as a reference molecule. We found that Ibu, Cur and NS-398 enhanced significantly doxo retention, cytotoxicity and apoptosis on resistant MES-SA/Doxo-5 cells when compared with doxo alone. In contrast, no significant changes were found in resistant cells treated with Sul-doxo combinations. Our results demonstrate that Ibu, Cur and NS-398 below their therapeutic plasma concentrations were able to overcome P-gp-mediated MDR in MES-SA/Dx-5 cells. These findings provide the rationale for clinical studies of NSAIDs and/or derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anti-cancer drugs in the treatment of human cancer.