MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study
Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521004901 |
| _version_ | 1818207993844465664 |
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| author | Zhuo-Xun Wu Qiu-Xu Teng Yuqi Yang Nikita Acharekar Jing-Quan Wang Min He Sabesan Yoganathan Jun Lin Jian Wang Zhe-Sheng Chen |
| author_facet | Zhuo-Xun Wu Qiu-Xu Teng Yuqi Yang Nikita Acharekar Jing-Quan Wang Min He Sabesan Yoganathan Jun Lin Jian Wang Zhe-Sheng Chen |
| author_sort | Zhuo-Xun Wu |
| collection | DOAJ |
| description | Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR. |
| first_indexed | 2024-12-12T04:37:45Z |
| format | Article |
| id | doaj.art-290b0cda90f24d6583e11b6b86866a8c |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-12T04:37:45Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-290b0cda90f24d6583e11b6b86866a8c2022-12-22T00:37:55ZengElsevierActa Pharmaceutica Sinica B2211-38352022-05-0112526092618MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo studyZhuo-Xun Wu0Qiu-Xu Teng1Yuqi Yang2Nikita Acharekar3Jing-Quan Wang4Min He5Sabesan Yoganathan6Jun Lin7Jian Wang8Zhe-Sheng Chen9Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Radiotherapy, the Affiliated Jiangyin People's Hospital of Nantong University, Jiangyin 214400, ChinaDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Anesthesiology, Stony Brook University Health Sciences Center, Stony Brook, NY 11794, USADepartment of Radiotherapy, the Affiliated Jiangyin People's Hospital of Nantong University, Jiangyin 214400, China; Corresponding authors.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA; Corresponding authors.Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.http://www.sciencedirect.com/science/article/pii/S2211383521004901MET inhibitorTepotinibMultidrug resistanceABCG2 transporterReversal agentCombination treatment |
| spellingShingle | Zhuo-Xun Wu Qiu-Xu Teng Yuqi Yang Nikita Acharekar Jing-Quan Wang Min He Sabesan Yoganathan Jun Lin Jian Wang Zhe-Sheng Chen MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study Acta Pharmaceutica Sinica B MET inhibitor Tepotinib Multidrug resistance ABCG2 transporter Reversal agent Combination treatment |
| title | MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study |
| title_full | MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study |
| title_fullStr | MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study |
| title_full_unstemmed | MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study |
| title_short | MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study |
| title_sort | met inhibitor tepotinib antagonizes multidrug resistance mediated by abcg2 transporter in vitro and in vivo study |
| topic | MET inhibitor Tepotinib Multidrug resistance ABCG2 transporter Reversal agent Combination treatment |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521004901 |
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