The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells
Abstract Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-89931-9 |
| _version_ | 1818843400805285888 |
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| author | Wang Yin Dongxi Xiang Tao Wang Yumei Zhang Cuong V. Pham Shufeng Zhou Guoqin Jiang Yingchun Hou Yimin Zhu Yinglu Han Liang Qiao Phuong H.-L. Tran Wei Duan |
| author_facet | Wang Yin Dongxi Xiang Tao Wang Yumei Zhang Cuong V. Pham Shufeng Zhou Guoqin Jiang Yingchun Hou Yimin Zhu Yinglu Han Liang Qiao Phuong H.-L. Tran Wei Duan |
| author_sort | Wang Yin |
| collection | DOAJ |
| description | Abstract Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization. |
| first_indexed | 2024-12-19T04:57:16Z |
| format | Article |
| id | doaj.art-67c194d8536544da957644e48e94460b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:57:16Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-67c194d8536544da957644e48e94460b2022-12-21T20:35:11ZengNature PortfolioScientific Reports2045-23222021-05-0111111310.1038/s41598-021-89931-9The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cellsWang Yin0Dongxi Xiang1Tao Wang2Yumei Zhang3Cuong V. Pham4Shufeng Zhou5Guoqin Jiang6Yingchun Hou7Yimin Zhu8Yinglu Han9Liang Qiao10Phuong H.-L. Tran11Wei Duan12School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin UniversityState Key Laboratory of Oncogenes and Related GenesCentre for Comparative Genomics, Murdoch UniversitySchool of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin UniversitySchool of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin UniversityDepartment of Chemical Engineering & Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao UniversityDepartment of General Surgery, Second Affiliated Hospital of Soochow UniversityLaboratory of Tumor Molecular and Cellular Biology, College of Life Sciences, Shaanxi Normal UniversityCAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of SciencesShanghai OneTar BiomedicineStorr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead HospitalSchool of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin UniversitySchool of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin UniversityAbstract Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.https://doi.org/10.1038/s41598-021-89931-9 |
| spellingShingle | Wang Yin Dongxi Xiang Tao Wang Yumei Zhang Cuong V. Pham Shufeng Zhou Guoqin Jiang Yingchun Hou Yimin Zhu Yinglu Han Liang Qiao Phuong H.-L. Tran Wei Duan The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells Scientific Reports |
| title | The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells |
| title_full | The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells |
| title_fullStr | The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells |
| title_full_unstemmed | The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells |
| title_short | The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells |
| title_sort | inhibition of abcb1 mdr1 or abcg2 bcrp enables doxorubicin to eliminate liver cancer stem cells |
| url | https://doi.org/10.1038/s41598-021-89931-9 |
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