Selonsertib (GS-4997), an ASK1 inhibitor, antagonizes multidrug resistance in ABCB1- and ABCG2-overexpressing cancer cells

• Published in: Cancer letters 2019-01, Vol.440-441, p.82-93
• Main Authors: Ji, Ning, Yang, Yuqi, Cai, Chao-Yun, Lei, Zi-Ning, Wang, Jing-Quan, Gupta, Pranav, Shukla, Suneet, Ambudkar, Suresh V., Kong, Dexin, Chen, Zhe-Sheng
• Format: Article
• Language: English
• Subjects: ABC transporters; ABCB1; ABCG2; Adenosine triphosphatase; Adenosine Triphosphatases - metabolism; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic drugs; Apoptosis; 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 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - biosynthesis; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; ATP-Binding cassette transporter; Cancer; Cancer therapies; 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; Chemotherapy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs; Enzyme inhibitors; HEK293 Cells; Humans; Kinases; Localization; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; MAP kinase; MAP Kinase Kinase Kinase 5 - antagonists & inhibitors; MAP Kinase Kinase Kinase 5 - metabolism; Mitoxantrone - pharmacokinetics; Models, Molecular; Multidrug resistance; Multidrug resistant organisms; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Paclitaxel - pharmacokinetics; Physiology; Protein Kinase Inhibitors - pharmacology; Protein transport; Protein-serine/threonine kinase; Proteins; Selonsertib
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.10.007

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. •Selonsertib, a selective ASK1 inhibitor, significantly overcome MDR in cancer.•Selonsertib stimulates the ATPase activity of ABCB1 and ABCG2.•Selonsertib interacts with the substrate-binding sites of both ABCB1 and ABCG2.•The combination of selonsertib with anticancer drugs could be a novel treatment strategy to evade MDR in cancer.