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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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Autores principales: Wang, Gangyang, Cao, Lingling, Jiang, Yafei, Zhang, Tao, Wang, Hongsheng, Wang, Zhuoying, Xu, Jing, Mao, Min, Hua, Yingqi, Cai, Zhengdong, Ma, Xiaojun, Hu, Shuo, Zhou, Chenghao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8801797/
https://www.ncbi.nlm.nih.gov/pubmed/35111065
http://dx.doi.org/10.3389/fphar.2021.798837
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author Wang, Gangyang
Cao, Lingling
Jiang, Yafei
Zhang, Tao
Wang, Hongsheng
Wang, Zhuoying
Xu, Jing
Mao, Min
Hua, Yingqi
Cai, Zhengdong
Ma, Xiaojun
Hu, Shuo
Zhou, Chenghao
author_facet Wang, Gangyang
Cao, Lingling
Jiang, Yafei
Zhang, Tao
Wang, Hongsheng
Wang, Zhuoying
Xu, Jing
Mao, Min
Hua, Yingqi
Cai, Zhengdong
Ma, Xiaojun
Hu, Shuo
Zhou, Chenghao
author_sort Wang, Gangyang
collection PubMed
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.
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spelling pubmed-88017972022-02-01 Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo Wang, Gangyang Cao, Lingling Jiang, Yafei Zhang, Tao Wang, Hongsheng Wang, Zhuoying Xu, Jing Mao, Min Hua, Yingqi Cai, Zhengdong Ma, Xiaojun Hu, Shuo Zhou, Chenghao Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2022-01-17 /pmc/articles/PMC8801797/ /pubmed/35111065 http://dx.doi.org/10.3389/fphar.2021.798837 Text en Copyright © 2022 Wang, Cao, Jiang, Zhang, Wang, Wang, Xu, Mao, Hua, Cai, Ma, Hu and Zhou. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Gangyang
Cao, Lingling
Jiang, Yafei
Zhang, Tao
Wang, Hongsheng
Wang, Zhuoying
Xu, Jing
Mao, Min
Hua, Yingqi
Cai, Zhengdong
Ma, Xiaojun
Hu, Shuo
Zhou, Chenghao
Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo
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 Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8801797/
https://www.ncbi.nlm.nih.gov/pubmed/35111065
http://dx.doi.org/10.3389/fphar.2021.798837
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