Masitinib reverses doxorubicin resistance in canine lymphoid cells by inhibiting the function of P-glycoprotein.
Overexpression of ABC-transporters including Pgp, MRP1, and BCRP has been associated with multidrug resistance (MDR) in both human and canine oncology. Therapeutic interventions to reverse MDR are limited, but include multidrug protocols and the temporary concomitant use of inhibitors of ABC-transporters. Recently, the use of tyrosine kinase inhibitors has been proposed to overcome MDR in human oncology. One of the tyrosine kinase inhibitors, masitinib, is licensed for veterinary use in the treatment of canine mast cell tumors. Therefore, this study aimed to assess the potential of masitinib to revert MDR in canine malignant lymphoma using an in vitro model with canine lymphoid cell lines. Masitinib had a mild antiproliferative effect on lymphoid cells, inhibited Pgp function at concentrations equal to or exceeding 1 μm and was able to reverse doxorubicin resistance. The current findings provide the rationale for a combined use of masitinib with doxorubicin in the treatment of dogs with doxorubicin-resistant malignant lymphoma but await confirmation in clinical trials.
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
M
M
Zandvliet
E
E
Teske
T
T
Chapuis
J
J
Fink-Gremmels
J A
JA
Schrickx
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism; D005786:Gene Expression Regulation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines; D020112:Rhodamine 123 / Q000378:metabolism; D013388:Succinimides / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D005452:Fluoresceins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013388:Succinimides; D013844:Thiazoles; C085925:calcein AM; D020112:Rhodamine 123; D004317:Doxorubicin; C526575:masitinib