One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells

Contino, Marialessandra; Guglielmo, Stefano; Riganti, Chiara; Antonello, Giulia; Perrone, Maria Grazia; Giampietro, Roberta; Rolando, Barbara; Fruttero, Roberta; Colabufo, Nicola Antonio

doi:10.1016/j.ejmech.2020.112843

Cited by 16 publications

(13 citation statements)

References 45 publications

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“…For this purpose, we studied the ability of selected compounds ( 19l , 19v , 19ao , 19af , and 19aj ) to compete with the transport of a profluorescent probe, Calcein-AM, that is also a P-gp substrate, in a cell line overexpressing P-gp (MDCK-MDR1 cell line) mimicking the BBB that was measured. Briefly, in MDCK-MDR1 cells, the pro-fluorescent Calcein-AM is not able to enter the cell membrane as effluxed by P-gp; in the presence of an agent able to interact with the pump (as a substrate), Calcein-AM enters the cell membrane and it is hydrolyzed, by the cytosol esterases, to the fluorescent Calcein (responsible for the fluorescence signal). − The results of this study are presented in Table . As observed, any of the tested compounds showed a significant interaction in MDCK-MDR1 cells with the Calcein-AM transport with respect to the P-gp reference substrate verapamil (EC 50 = 0.50 μM) .…”

Section: Results and Discussionmentioning

confidence: 89%

“…Calcein cell accumulation was evaluated by following a previously described method. − The MDCK-MDR1 cell line (30,000 cells per well) was seeded into a 96-well black culture plate with 100 μL of the medium and allowed to become confluent overnight. Test compounds (100 μL) were solubilized in the culture medium and added to monolayers, with final concentrations ranging from 0.1 to 100 μM.…”

Section: Methodsmentioning

confidence: 99%

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Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

et al. 2022

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We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A 1 AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure–activity and structure–selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R 4 and R 6 of the pyrimidine core but most importantly the prominent role to the unprecedented A 1 AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure–activity relationship trends on both A 1 and A 2A ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.

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Section: Results and Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

et al. 2022

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“…The assay was performed in HGC27-S/R and KATOIII-S/R cells 48 hrs upon treatment, as already reported with a minor modification ( 26 ). Briefly, the cells were seeded into 96-well plates at density of 15000 cells/well in a volume of 100 μL of fresh medium.…”

Section: Methodsmentioning

confidence: 99%

The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines

et al. 2023

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IntroductionPaclitaxel (PTX) interferes with microtubule architecture by binding to β-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTX-mediated resistance in gastric cancer (GC) cells. MethodsPTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. ResultsThus, the key feature of PTX-resistant cells was the overexpression of pro-angiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBβIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines.Discussion These findings were in line with a greater sensitivity of resistant cells to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBβIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and pro-apoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment.

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“…The experiments were carried out as described by Contino et al with minor modifications. [49] The MDCK-MDR1 cells seeded into 96well microplate in 100 μL of complete medium at a density 2 × 10 4 cells/well were incubated overnight (O/N) in a humidified atmosphere 5 % CO 2 at 37 °C. The medium was removed and 100 μL of complete medium either alone or containing different concentrations of test compounds were added.…”

Section: Atplite Assaymentioning

confidence: 99%

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

et al. 2022

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Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC 50 values in the nanomolar range (1 d, 1 e, 2 a, 2 c, 2 e). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.

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One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells

Cited by 16 publications

References 45 publications

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

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One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells

Cited by 16 publications

References 45 publications

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

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Product

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Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists