M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, w...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00674/full |
| _version_ | 1811212769441087488 |
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| author | Zhuo-Xun Wu Zheng Peng Yuqi Yang Jing-Quan Wang Qiu-Xu Teng Zi-Ning Lei Yi-Ge Fu Ketankumar Patel Lili Liu Lizhu Lin Chang Zou Zhe-Sheng Chen |
| author_facet | Zhuo-Xun Wu Zheng Peng Yuqi Yang Jing-Quan Wang Qiu-Xu Teng Zi-Ning Lei Yi-Ge Fu Ketankumar Patel Lili Liu Lizhu Lin Chang Zou Zhe-Sheng Chen |
| author_sort | Zhuo-Xun Wu |
| collection | DOAJ |
| description | M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR. |
| first_indexed | 2024-04-12T05:36:01Z |
| format | Article |
| id | doaj.art-bd321e0b0df0472487c921880aa34631 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T05:36:01Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-bd321e0b0df0472487c921880aa346312022-12-22T03:45:53ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-05-011010.3389/fonc.2020.00674528100M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer CellsZhuo-Xun Wu0Zheng Peng1Yuqi Yang2Jing-Quan Wang3Qiu-Xu Teng4Zi-Ning Lei5Yi-Ge Fu6Ketankumar Patel7Lili Liu8Lizhu Lin9Chang Zou10Zhe-Sheng Chen11Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesThe Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, ChinaDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesGuangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, ChinaCancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, ChinaDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United StatesM3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.https://www.frontiersin.org/article/10.3389/fonc.2020.00674/fullATP-binding cassette (ABC) transporterM3814nedisertibABCG2multidrug resistance (MDR) |
| spellingShingle | Zhuo-Xun Wu Zheng Peng Yuqi Yang Jing-Quan Wang Qiu-Xu Teng Zi-Ning Lei Yi-Ge Fu Ketankumar Patel Lili Liu Lizhu Lin Chang Zou Zhe-Sheng Chen M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells Frontiers in Oncology ATP-binding cassette (ABC) transporter M3814 nedisertib ABCG2 multidrug resistance (MDR) |
| title | M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells |
| title_full | M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells |
| title_fullStr | M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells |
| title_full_unstemmed | M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells |
| title_short | M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells |
| title_sort | m3814 a dna pk inhibitor modulates abcg2 mediated multidrug resistance in lung cancer cells |
| topic | ATP-binding cassette (ABC) transporter M3814 nedisertib ABCG2 multidrug resistance (MDR) |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00674/full |
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