title: Simotinib as a modulator of P-glycoprotein: substrate, inhibitor, or inducer?
abstract: As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug-drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high-performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment.
authors.affiliation: aThe School of Pharmaceutical Sciences in Central South University bState Key Laboratory of Medical Genetics, School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Huang
authors.forename: Cheng
authors.initials: C
authors.lastname: Shen
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Chen
authors.forename: Huiwen
authors.initials: H
authors.lastname: Yan
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
authors.forename: Qubo
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011799:Quinazolines; D013141:Spiro Compounds; C000591834:N-(3-chloro-4-fluorophenyl)-6-(2-(5, 8-dioxa-11-azadispiro(2.0.4.3)undec-11-yl)ethoxy)-7-methoxy-4-quinazolinamine; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D017239:Paclitaxel