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Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
A more potent and specific inhibitor of P-gp, zosuquidar, is currently being tested more extensively in AML (116–118). This drug is specific for P-gp and thus has less potential for drug interactions with cytotoxins than other MDR modulators (119–121).
Comprehensive characterization and optimization of Caco-2 cells enabled the development of a miniaturized 96-well permeability assay
Published in Xenobiotica, 2022
Xianmei Cai, Shivani Patel, Chunli Huang, Anthony Paiva, Yongnian Sun, Gregory Barker, Harold Weller, Wilson Shou
Caco-2 cells were washed once with calcium-magnesium free PBS buffer and detached from the flask with 0.05% Trypsin for about 5 min. Then culture media with 10% FBS was added to inactivate Trypsin. The single cell suspension was made by pipetting up and down a few times. Cells were counted, and the total cell number was calculated. After centrifugation and supernatant removal, the cell pellet was resuspended into PBS solution to a final concentration of 5- 10 million cells/mL. 100uL of cell suspension was added into each tube. Either 1 µL DMSO or Pgp inhibitor Zosuquidar with a final concentration at 5 µM was added into tubes and mixed well.
Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Abeer H. A. Abdelhafiz, Rabah A. T. Serya, Deena S. Lasheen, Nessa Wang, Mansour Sobeh, Michael Wink, Khaled A. M. Abouzid
To our knowledge, there are 50 human ABC transporters genes encoding the formation of membrane-bound pumps which bind and transport a diverse set of substrates7. Among the various MDR-related ABC transporters, the most prominent members are ABCB14, ABCC1 and ABCG28,9. ABCB1 drug transporter (also known as P-glycoprotein or MDR1) is a well-studied and characterised member of the ABCB superfamily, which is responsible for the efflux of cytotoxic drugs thus decreasing their intracellular concentration10. The first generation ABCB1 inhibitor, verapamil (1) (Figure 1), was reported to overcome P-glycoprotein mediated drug efflux of Vinca alkaloids. However, it was never used clinically to overcome MDR due to its devastating side effects as nausea, vomiting and abdominal pain11. More recently developed ABCB1 inhibitors as zosuquidar (2) showed less adverse effects, but no improvement in the treatment was recorded during clinical trials12. So far, various possible reasons contribute to the failure of these tested ABCB1 inhibitors. Lack of specificity and severe adverse effects are the suggested main contributors to the failure of such inhibitors13. Interestingly, a recent study reported the discovery of a new ABCB1 inhibitor WS-691 (3) which was used in combination with PTX (paclitaxel) in PTX-resistant cells where ABCB1 are overexpressed. The use of a non-toxic dose of WS-691 (20 µM) successfully decreased the IC50 of PTX from 4.23 to 0.022 µM without evidence to exhibit cytotoxic activity when used alone10. Remarkably, ABCB1 transporters are ubiquitously overexpressed in many MDR cancer cells14–16. Consequently, ABCB1 inhibition is a rewarding target to overcome failure of cytotoxic agents due to MDR.
Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
A randomized phase II clinical trial compared docetaxel administration with or without zosuquidar in metastatic breast cancer patients. No significant difference in overall survival or response rate was observed in docetaxel plus zosuquidar-treated group compared with docetaxel alone [62]. Seventeen patients with breast carcinoma received doxorubicin or taxane chemotherapy regimens with or without tariquidar. The results revealed that tariquidar did not offer the potential to reverse resistance to doxorubicin or taxane chemotherapy [63].