Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo
Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and d...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521000034 |
| _version_ | 1819085349393006592 |
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| author | Xu Wu Chun Yin Jiang Ma Stella Chai Chunyuan Zhang Sheng Yao Onat Kadioglu Thomas Efferth Yang Ye Kenneth Kin-Wah To Ge Lin |
| author_facet | Xu Wu Chun Yin Jiang Ma Stella Chai Chunyuan Zhang Sheng Yao Onat Kadioglu Thomas Efferth Yang Ye Kenneth Kin-Wah To Ge Lin |
| author_sort | Xu Wu |
| collection | DOAJ |
| description | Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of Marsdenia tenacissima (M. tenacissima) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of M. tenacissima in combinational chemotherapy. |
| first_indexed | 2024-12-21T21:02:57Z |
| format | Article |
| id | doaj.art-5f23428dd85e423899251c55eb3bb20f |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-21T21:02:57Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-5f23428dd85e423899251c55eb3bb20f2022-12-21T18:50:24ZengElsevierActa Pharmaceutica Sinica B2211-38352021-07-0111718851902Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivoXu Wu0Chun Yin1Jiang Ma2Stella Chai3Chunyuan Zhang4Sheng Yao5Onat Kadioglu6Thomas Efferth7Yang Ye8Kenneth Kin-Wah To9Ge Lin10School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, China; Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, ChinaSchool of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, ChinaSchool of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, ChinaSchool of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, ChinaSchool of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, ChinaJoint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, China; State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaDepartment of Pharmaceutical Biology, Johannes Gutenberg University, Mainz 55099, GermanyDepartment of Pharmaceutical Biology, Johannes Gutenberg University, Mainz 55099, GermanyJoint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, China; State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSchool of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Corresponding authors.School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Hong Kong 999077, China; Corresponding authors.Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of Marsdenia tenacissima (M. tenacissima) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of M. tenacissima in combinational chemotherapy.http://www.sciencedirect.com/science/article/pii/S2211383521000034Multidrug resistanceABCB1PolyoxypregnaneCombination chemotherapyMarsdenia tenacissima |
| spellingShingle | Xu Wu Chun Yin Jiang Ma Stella Chai Chunyuan Zhang Sheng Yao Onat Kadioglu Thomas Efferth Yang Ye Kenneth Kin-Wah To Ge Lin Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo Acta Pharmaceutica Sinica B Multidrug resistance ABCB1 Polyoxypregnane Combination chemotherapy Marsdenia tenacissima |
| title | Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| title_full | Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| title_fullStr | Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| title_full_unstemmed | Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| title_short | Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| title_sort | polyoxypregnanes as safe potent and specific abcb1 inhibitory pro drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo |
| topic | Multidrug resistance ABCB1 Polyoxypregnane Combination chemotherapy Marsdenia tenacissima |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521000034 |
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