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Selonsertib (GS-4997), an ASK1 inhibitor, antagonizes multidrug resistance in ABCB1- and ABCG2-overexpressing cancer cells.
- Source :
-
Cancer letters [Cancer Lett] 2019 Jan; Vol. 440-441, pp. 82-93. Date of Electronic Publication: 2018 Oct 10. - Publication Year :
- 2019
-
Abstract
- Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for the development of multidrug resistance (MDR). Selonsertib, a serine/threonine kinase inhibitor, targets apoptosis signal-regulating kinase 1 (ASK1) and is now in phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH). In this study, we investigated whether selonsertib could reverse MDR-mediated by ABC transporters, including ABCB1, ABCG2, ABCC1 and ABCC10. The results showed that selonsertib significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR-mediated by ABCC1 or ABCC10. Mechanism studies indicated that the reversal effect of selonsertib was related to the attenuation of the efflux activity of ABCB1 and ABCG2 transporters, without the protein level decrease or change in the subcellular localization of ABCB1 or ABCG2. Selonsertib stimulated the ATPase activity of ABCB1 and ABCG2 in a concentration-dependent manner, and in silico docking study showed selonsertib could interact with the substrate-binding sites of both ABCB1 and ABCG2. This study provides a clue into a novel treatment strategy, which includes a combination of selonsertib with antineoplastic drugs to attenuate MDR-mediated by ABCB1 or ABCG2 in cancer cells overexpressing these transporters.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B biosynthesis
ATP Binding Cassette Transporter, Subfamily B metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2 biosynthesis
ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism
Adenosine Triphosphatases metabolism
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents, Phytogenic pharmacokinetics
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell metabolism
Cell Line, Tumor
Colonic Neoplasms drug therapy
Colonic Neoplasms metabolism
Drug Resistance, Multiple
Drug Resistance, Neoplasm
HEK293 Cells
Humans
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
MAP Kinase Kinase Kinase 5 antagonists & inhibitors
MAP Kinase Kinase Kinase 5 metabolism
Mitoxantrone pharmacokinetics
Models, Molecular
Neoplasm Proteins biosynthesis
Neoplasm Proteins metabolism
Neoplasms metabolism
Paclitaxel pharmacokinetics
Protein Kinase Inhibitors pharmacology
ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors
Antibodies, Monoclonal, Humanized pharmacology
Neoplasm Proteins antagonists & inhibitors
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 440-441
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 30315846
- Full Text :
- https://doi.org/10.1016/j.canlet.2018.10.007