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 non-steroidal anti-inflammatory drugs (NSAIDs) such as Curcumin (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.
Angelini
Antonio
A
Università Gabriele D'Annunzio, Facoltà di Medicina e Chirurgia, Centro di Scienze dell'Invecchiamento (Ce.S.I.), Campus Universitario, Chieti Scalo, Italy. aangelini@unich.it
Iezzi
Manuela
M
Di Febbo
Concetta
C
Di Ilio
Carmine
C
Cuccurullo
Franco
F
Porreca
Ettore
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004317:Doxorubicin