scholarly journals Screening novel CNS drug candidates for P-glycoprotein interactions using the cell line iP-gp: in vitro efflux ratios from iP-gp and MDCK-MDR1 monolayers compared to brain distribution data from mice

2021 ◽  
Author(s):  
Burak Ozgür ◽  
Lasse Saaby ◽  
Christian Janfelt ◽  
Kristine Langthaler ◽  
Elin Eneberg ◽  
...  
Keyword(s):  
Cell Line ◽  
Distribution Data ◽  
Brain Distribution ◽  
Drug Candidates ◽  
P Glycoprotein

In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin

2000 ◽  
Vol 12 (2) ◽  
pp. 85-93 ◽  
Author(s):  
Elizabeth C.M. de Lange ◽  
Sandrine Marchand ◽  
Dirk-Jan van den Berg ◽  
Inez C.J. van der Sandt ◽  
Albertus G. de Boer ◽  
...  
Keyword(s):  
Brain Distribution ◽  
Efflux Transporter ◽  
P Glycoprotein

scholarly journals IPEC-J2 rMdr1a, a New Cell Line with Functional Expression of Rat P-glycoprotein Encoded by Rat Mdr1a for Drug Screening Purposes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 673 ◽  
Author(s):  
Lasse Saaby ◽  
Josefine Trasborg ◽  
Mikkel A. Rasmussen ◽  
Bjørn Holst ◽  
Birger Brodin
Keyword(s):  
Cell Line ◽  
Efflux Pump ◽  
Cell Model ◽  
Drug Distribution ◽  
Functional Expression ◽  
Established Cell Line ◽  
Multidrug Resistance Gene ◽  
Western Blots ◽  
P Glycoprotein

The efflux pump P-glycoprotein (P-gp) affects drug distribution after absorption in humans and animals. P-gp is encoded by the multidrug resistance gene (MDR1) gene in humans, while rodents (the most common preclinical animal model) express the two isoforms Mdr1a and Mdr1b. Differences in substrate selectivity has also been reported. Our aim was to generate an in vitro cell model with tight barrier properties, expressing functional rat Mdr1a P-gp, as an in vitro tool for investigating species differences. The IPEC-J2 cell line forms extremely tight monolayers and was transfected with a plasmid carrying the rat Mdr1a gene sequence. Expression and P-gp localization at the apical membrane was demonstrated with Western blots and immunocytochemistry. Function of P-gp was shown through digoxin transport experiments in the presence and absence of the P-gp inhibitor zosuquidar. Bidirectional transport experiments across monolayers of the IPEC-J2 rMDR1a cell line and the IPEC-J2 MDR1 cell line, expressing human P-gp, showed comparable magnitude of transport in both the absorptive and efflux direction. We conclude that the newly established IPEC-J2 rMdr1a cell line, in combination with our previously established cell line IPEC-J2 MDR1, has the potential to be a strong in vitro tool to compare P-gp substrate profiles of rat and human P-gp.

IN VITRO P-GLYCOPROTEIN INHIBITION ASSAYS FOR ASSESSMENT OF CLINICAL DRUG INTERACTION POTENTIAL OF NEW DRUG CANDIDATES: A RECOMMENDATION FOR PROBE SUBSTRATES

2006 ◽  
Vol 34 (5) ◽  
pp. 786-792 ◽  
Author(s):  
Jarkko Rautio ◽  
Joan E. Humphreys ◽  
Lindsey O. Webster ◽  
Anand Balakrishnan ◽  
John P. Keogh ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Interaction Potential ◽  
Drug Candidates ◽  
New Drug ◽  
P Glycoprotein ◽  
Glycoprotein Inhibition ◽  
Clinical Drug

scholarly journals Enhanced Cytotoxic Effect of Doxorubicin Conjugated to Glutathione-Stabilized Gold Nanoparticles in Canine Osteosarcoma—In Vitro Studies

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3487
Author(s):  
Anna Małek ◽  
Bartłomiej Taciak ◽  
Katarzyna Sobczak ◽  
Agnieszka Grzelak ◽  
Michał Wójcik ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Cell Line ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Negative Control ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Ic50 Values ◽  
Anti Tumor Activity

Osteosarcoma (OSA) is the most common malignant bone neoplasia in humans and dogs. In dogs, treatment consists of surgery in combination with chemotherapy (mostly carboplatin and/or doxorubicin (Dox)). Chemotherapy is often rendered ineffective by multidrug resistance. Previous studies have revealed that Dox conjugated with 4 nm glutathione-stabilized gold nanoparticles (Au-GSH-Dox) enhanced the anti-tumor activity and cytotoxicity of Dox in Dox-resistant feline fibrosarcoma cell lines exhibiting high P-glycoprotein (P-gp) activity. The present study investigated the influence of Au-GSH-Dox on the canine OSA cell line D17 and its relationship with P-gp activity. A human Dox-sensitive OSA cell line, U2OS, served as the negative control. Au-GSH-Dox, compared to free Dox, presented a greater cytotoxic effect on D17 (IC50 values for Au-GSH-Dox and Dox were 7.9 μg/mL and 15.2 μg/mL, respectively) but not on the U2OS cell line. All concentrations of Au-GSH (ranging from 10 to 1000 μg/mL) were non-toxic in both cell lines. Inhibition of the D17 cell line with 100 μM verapamil resulted in an increase in free Dox but not in intracellular Au-GSH-Dox. The results indicate that Au-GSH-Dox may act as an effective drug in canine OSA by bypassing P-gp.

scholarly journals Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4286-4294 ◽  
Author(s):  
R O'Connor ◽  
C Liu ◽  
CA Ferris ◽  
BC Guild ◽  
BA Teicher ◽  
...  
Keyword(s):  
Cell Line ◽  
Residual Disease ◽  
Severe Combined Immunodeficiency ◽  
Disease Stage ◽  
Good Effect ◽  
Retroviral Infection ◽  
P Glycoprotein ◽  
Mdr 1

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P- glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr- 1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Na-malwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.

Mitotracker Green Is a P-Glycoprotein Substrate

2003 ◽  
Vol 23 (4) ◽  
pp. 199-212 ◽  
Author(s):  
Luis F. Marques-Santos ◽  
José G. P. Oliveira ◽  
Raquel C. Maia ◽  
Vivian M. Rumjanek
Keyword(s):  
Cell Line ◽  
Fluorescent Dyes ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Normal Tissues ◽  
P Glycoprotein ◽  
Erythroleukemic Cell ◽  
Erythroleukemic Cell Line ◽  
Mitotracker Green

P-glycoprotein has a widespread expression on normal tissues. The protein has also been strongly associated with the multidrug resistance phenotype (MDR) on tumor cells. The employment of flow cytometry and confocal microscopy has contributed to the discovery and application of new particular fluorescent dyes. Nevertheless, several studies are being performed in different cellular types neglecting the expression activity of MDR proteins. Because many fluorochromes have been reported as P-glycoprotein substrates, an especial attention must be given to the properties of new dyes in the presence of MDR proteins. Flow cytometric analyzes of Mitotracker Green (MTG) fluorescence profile were performed in a human erythroleukemic cell line and its resistant counterpart. In this report we demonstrated that MTG, a probe used to evaluate the mitochondrial mass, is a P-glycoprotein substrate and its staining profile is dependent on the activity of this protein. In vitro studies on a human erythroleukemic cell line and its resistant counterpart revealed that MDR modulators (Cyclosporin A, Verapamil, and Trifluoperazine) alter the MTG fluorescence pattern on a resistant cell line. The findings suggest that attention should be given to the expression of P-glycoprotein when performing an evaluation of mitochondria properties with MTG.

scholarly journals Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Anna Jaromin ◽  
Anna Czopek ◽  
Silvia Parapini ◽  
Nicoletta Basilico ◽  
Ernest Misiak ◽  
...  
Keyword(s):  
Cell Line ◽  
Antimalarial Activity ◽  
In Vitro Cytotoxicity ◽  
Drug Candidates ◽  
Bicyclic System ◽  
Keratinocyte Cell ◽  
Heterocyclic Derivatives ◽  
Low Toxicity ◽  
Physicochemical Characterisation

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of P. falciparum—the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC50 between 2424.15–5648.07 ng/mL (4.98–11.95 µM)), compared to the D10 strain (6202.00–9659.70 ng/mL (12.75–19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of P. falciparum, appear to be interesting antimalarial drug candidates.

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