Nilotinib counteracts P-glycoprotein-mediated multidrug resistance and synergizes the antitumoral effect of doxorubicin in soft tissue sarcomas

• Published in: PloS one Vol. 7; no. 5; p. e37735
• Main Authors: Villar, Victor Hugo, Vögler, Oliver, Martínez-Serra, Jordi, Ramos, Rafael, Calabuig-Fariñas, Silvia, Gutiérrez, Antonio, Barceló, Francisca, Martín-Broto, Javier, Alemany, Regina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.05.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biology; Bone cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell number; Cell Proliferation - drug effects; Chemotherapy; Development and progression; Doxorubicin; Doxorubicin - pharmacology; Drug dosages; Drug Resistance, Multiple; Drug Synergism; Drugs; Efflux; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glycoproteins; Granulocytes; Health aspects; Hematology; Humans; Imatinib; Inhibition; Kinases; Leukemia; MAP kinase; Material requirements planning; Medicine; Microbial drug resistance; Molecular modelling; MRP1 protein; Multidrug resistance; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug resistant organisms; P-Glycoprotein; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; Sarcoma; Sarcoma - metabolism; Signal Transduction - drug effects; Synergistic effect; Synovial sarcoma; Tissues; Toxicity; Tumors; Tyrosine; Balearic Islands; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037735

The therapeutic effect of doxorubicin (DXR) in the treatment of soft tissue sarcomas (STS) is limited by its toxicity and the development of multidrug resistance (MDR), the latter mainly induced by high expression of efflux pumps (e.g., P-glycoprotein [P-gp]). Therefore, the search for alternative therapies, which sensitize these tumors to chemotherapy while maintaining a low toxicity profile, is a rational approach. We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of the tyrosine kinase inhibitors, nilotinib and imatinib, as single agents or in combination with DXR, in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound nilotinib (1-10 µM) was more potent than imatinib inhibiting the growth of SK-UT-1 and SW982 cells by 33.5-59.6%, respectively. Importantly, only nilotinib synergized the antitumoral effect of DXR (0.05-0.5 µM) by at least 2-fold, which clearly surpassed the mere sum of effects according to isobolographic analysis. Moreover, nilotinib in combination with DXR had a sustained effect on cell number (-70.3±5.8%) even 12 days after withdrawal of drugs compared to DXR alone. On the molecular level, only nilotinib fully blocked FBS-induced ERK1 and p38 MAPK activation, hence, reducing basal and DXR-induced up-regulation of P-gp levels. Moreover, efflux activity of the MDR-related proteins P-gp and MRP-1 was inhibited, altogether resulting in intracellular DXR retention. In high-risk STS tumors 53.8% and 15.4% were positive for P-gp and MRP-1 expression, respectively, with high incidence of P-gp in synovial sarcoma (72.7%). In summary, nilotinib exhibits antiproliferative effects on cellular models of STS and sensitizes them to DXR by reverting DXR-induced P-gp-mediated MDR and inhibiting MRP-1 activity, leading to a synergistic effect with potential for clinical treatment.