sdz-psc-833 and tryptoquivaline

Active efflux proteins such as P-glycoprotein (P-gp) are thought to have a protective role in the intestinal tract by preventing xenotoxin absorption. Some bacteria also need to adhere to the intestinal tract before causing disease through adhesin secretion. Thus, this study was initiated to examine whether any association exists between bacterial adhesion.. Three human cell lines (Caco2, RKO, and MCF7), and 6 species of bacteria were used in this study (Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Klebsiella pneumoniae, Clostridium sporogenes and Pseudomonas aeruginosa). Following incubation of our cells with active efflux inhibitors, bacteria incubated with a stable fluorescent dye were co-incubated at 37°C for various times up to 240min. Fluorescence intensity was used to compare bacterial attachment to these cell lines with either normal efflux protein expression or with induction or inhibition of efflux proteins.. P-gp inhibition by either PSC-833 or GF120918 resulted in a significant increase of all bacterial attachment to Caco2 cells up to 3 fold. RKO cells and MCF7 cells did not alter their bacterial attachment with PSC-833. Fumitremorgen C, a dedicated BCRP inhibitor had no effect. In addition, rifampicin, a P-gp inducer, resulted in some limited reduction in Salmonella and Klebsiella attachment only.. These results indicate P-gp expression may contribute to the resistance of potential bacterial toxicity, by preventing them adhering to human enterocytes cells in the gastrointestinal tract, which may reduce the risk or intensity of gastrointestinal disorders.

Topics: Acridines; Analysis of Variance; Antibiotics, Antitubercular; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bacterial Adhesion; Caco-2 Cells; Clostridium; Cyclosporins; Drug Resistance, Multiple, Bacterial; Escherichia coli; Fluorescence; Humans; Immunosuppressive Agents; Indoles; Klebsiella pneumoniae; Neoplasm Proteins; Pseudomonas aeruginosa; Rifampin; Salmonella typhimurium; Staphylococcus aureus; Tetrahydroisoquinolines

ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity.. MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity.. Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters.. A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.

Topics: Aniline Compounds; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cyclosporins; Dasatinib; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Fusion Proteins, bcr-abl; Humans; Indoles; K562 Cells; Neoplasm Proteins; Neoplasms; Nitriles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Substrate Specificity; Thiazoles

Overexpression of the transporter ABCG2, also known as breast cancer resistance protein and mitoxantrone resistance protein, can confer resistance to a variety of cytostatic drugs, such as mitoxantrone, topotecan, doxorubicin, and daunorubicin. This study analyzes the ABCG2 expression and activity in 46 human de novo acute lymphoblastic leukemia B- and T-lineage (ALL) samples.. ABCG2 expression was measured flow cytometrically with the BXP-34 monoclonal antibody. ABCG2 functional activity was determined flow cytometrically by measuring mitoxantrone accumulation in combination with the ABCG2 inhibitor fumitremorgin C (FTC). To determine a possible effect of the transporters P-glycoprotein and multidrug resistance-associated protein (MRP1 and MRP2) on mitoxantrone accumulation, the accumulation was investigated in the presence of the P-glycoprotein inhibitor PSC 833 and MRP inhibitor MK-571. The ABCG2 gene was sequenced to investigate the amino acid at position 482.. In B-lineage ALL (n = 23), the median BXP-34:IgG1 ratio was higher, namely 2.4 (range, 1.7-3.7), than in T-lineage ALL (n = 23; 1.9; range, 1.2-6.6; P = 0.003). The addition of FTC to mitoxantrone treatment caused a median increase in mitoxantrone accumulation of 21% (range, 0-140%) in B-lineage ALL. In T-lineage ALL, this FTC effect was less pronounced (5%; range, 0-256%; P = 0.013). The influence of FTC on mitoxantrone accumulation correlated with ABCG2 protein expression (r = 0.52; P < 0.001; n = 43). The increase in mitoxantrone accumulation, when FTC was added to cells treated with both PSC 833 and MK-571, correlated with the ABCG2 expression in B-lineage ALL but not in T-lineage ALL. Sequencing the ABCG2 gene revealed no ABCG2 mutation at position 482 in patients who accumulated more rhodamine after FTC.. This study shows that ABCG2 is expressed higher and functionally more active in B-lineage than in T-lineage ALL.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bronchodilator Agents; Burkitt Lymphoma; Child; Child, Preschool; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Flow Cytometry; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Neoplastic; Humans; Indoles; Infant; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Mitoxantrone; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Propionates; Quinolines; Tumor Cells, Cultured