Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo
Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.798837/full |
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| author | Gangyang Wang Gangyang Wang Lingling Cao Yafei Jiang Yafei Jiang Tao Zhang Tao Zhang Hongsheng Wang Hongsheng Wang Zhuoying Wang Zhuoying Wang Jing Xu Jing Xu Min Mao Min Mao Yingqi Hua Yingqi Hua Zhengdong Cai Zhengdong Cai Xiaojun Ma Xiaojun Ma Shuo Hu Shuo Hu Chenghao Zhou Chenghao Zhou |
| author_facet | Gangyang Wang Gangyang Wang Lingling Cao Yafei Jiang Yafei Jiang Tao Zhang Tao Zhang Hongsheng Wang Hongsheng Wang Zhuoying Wang Zhuoying Wang Jing Xu Jing Xu Min Mao Min Mao Yingqi Hua Yingqi Hua Zhengdong Cai Zhengdong Cai Xiaojun Ma Xiaojun Ma Shuo Hu Shuo Hu Chenghao Zhou Chenghao Zhou |
| author_sort | Gangyang Wang |
| collection | DOAJ |
| description | Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs. |
| first_indexed | 2024-12-21T01:02:51Z |
| format | Article |
| id | doaj.art-b3fe8990c2384f8ba53188f09c75650c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T01:02:51Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-b3fe8990c2384f8ba53188f09c75650c2022-12-21T19:21:09ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-01-011210.3389/fphar.2021.798837798837Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In VivoGangyang Wang0Gangyang Wang1Lingling Cao2Yafei Jiang3Yafei Jiang4Tao Zhang5Tao Zhang6Hongsheng Wang7Hongsheng Wang8Zhuoying Wang9Zhuoying Wang10Jing Xu11Jing Xu12Min Mao13Min Mao14Yingqi Hua15Yingqi Hua16Zhengdong Cai17Zhengdong Cai18Xiaojun Ma19Xiaojun Ma20Shuo Hu21Shuo Hu22Chenghao Zhou23Chenghao Zhou24Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Rehabilitation, Shanghai Fifth Rehabilitation Hospital, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaDepartment of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Bone Tumor Institute, Shanghai, ChinaOverexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.https://www.frontiersin.org/articles/10.3389/fphar.2021.798837/fullanlotinibosteosarcomamultidrug resistanceATP-binding cassette (ABC) transporterP-glycoprotein |
| spellingShingle | Gangyang Wang Gangyang Wang Lingling Cao Yafei Jiang Yafei Jiang Tao Zhang Tao Zhang Hongsheng Wang Hongsheng Wang Zhuoying Wang Zhuoying Wang Jing Xu Jing Xu Min Mao Min Mao Yingqi Hua Yingqi Hua Zhengdong Cai Zhengdong Cai Xiaojun Ma Xiaojun Ma Shuo Hu Shuo Hu Chenghao Zhou Chenghao Zhou Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo Frontiers in Pharmacology anlotinib osteosarcoma multidrug resistance ATP-binding cassette (ABC) transporter P-glycoprotein |
| title | Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo |
| title_full | Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo |
| title_fullStr | Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo |
| title_full_unstemmed | Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo |
| title_short | Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo |
| title_sort | anlotinib reverses multidrug resistance mdr in osteosarcoma by inhibiting p glycoprotein pgp1 function in vitro and in vivo |
| topic | anlotinib osteosarcoma multidrug resistance ATP-binding cassette (ABC) transporter P-glycoprotein |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.798837/full |
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