Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro
Background Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. Investigating the mechanism of TAX resistance of breast cancer cells and developing...
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| Format: | Article |
| Language: | English |
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BioMed Central
2018
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| Online Access: | http://hdl.handle.net/1721.1/118308 https://orcid.org/0000-0001-8131-2468 https://orcid.org/0000-0003-0551-1208 |
| _version_ | 1826190401285914624 |
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| author | Yang, Liu Tian, Yanhua Leong, Wei Sun Song, Heng Yang, Wei Wang, Meiqi Wang, Xinle Kong, Jing Shan, Baoen Song, Zhengchuan |
| author2 | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science |
| author_facet | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Yang, Liu Tian, Yanhua Leong, Wei Sun Song, Heng Yang, Wei Wang, Meiqi Wang, Xinle Kong, Jing Shan, Baoen Song, Zhengchuan |
| author_sort | Yang, Liu |
| collection | MIT |
| description | Background
Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. Investigating the mechanism of TAX resistance of breast cancer cells and developing the strategy improving its therapeutic efficiency are crucial to breast cancer cure.
Methods and Results
We here report an elegant nanoparticle (NP)-based technique that realizes efficient breast cancer treatment of TAX. Using lentiviral vector-mediated gene knockdown, we first demonstrated that TAX therapeutic efficiency was closely correlated with metadherin (MTDH) gene expression in breast cancer cell lines. This finding was also supported by efficacy of TAX treatment in breast cancer patients from our clinical studies. Specifically, TAX treatment became more effective when MTDH expression was decreased in MCF-7 cancer cells by the blocking nuclear factor-kappa B (NF-κB) pathway. Based on these findings, we subsequently synthesized a polymeric NP that could co-deliver MTDH-small interfering RNA (MTDH–siRNA) and TAX into the breast cancer tumors in tumor-bearing mice. The NPs were composed of a cationic copolymer, which wrapped TAX in the inside and adsorbed the negatively charged siRNA on their surface with high drug-loading efficiency and good stability.
Conclusions
NP-based co-delivery approach can effectively knock down the MTDH gene both in vitro and in vivo, which dramatically inhibits breast tumor growth, achieving effective TAX chemotherapy treatment without overt side effects. This study provides a potential therapeutic strategy for the treatment of a wide range of solid tumors highly expressing MTDH. |
| first_indexed | 2024-09-23T08:39:42Z |
| format | Article |
| id | mit-1721.1/118308 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:39:42Z |
| publishDate | 2018 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1183082022-09-30T10:21:55Z Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro Yang, Liu Tian, Yanhua Leong, Wei Sun Song, Heng Yang, Wei Wang, Meiqi Wang, Xinle Kong, Jing Shan, Baoen Song, Zhengchuan Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Research Laboratory of Electronics Leong, Wei Sun Kong, Jing Background Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. Investigating the mechanism of TAX resistance of breast cancer cells and developing the strategy improving its therapeutic efficiency are crucial to breast cancer cure. Methods and Results We here report an elegant nanoparticle (NP)-based technique that realizes efficient breast cancer treatment of TAX. Using lentiviral vector-mediated gene knockdown, we first demonstrated that TAX therapeutic efficiency was closely correlated with metadherin (MTDH) gene expression in breast cancer cell lines. This finding was also supported by efficacy of TAX treatment in breast cancer patients from our clinical studies. Specifically, TAX treatment became more effective when MTDH expression was decreased in MCF-7 cancer cells by the blocking nuclear factor-kappa B (NF-κB) pathway. Based on these findings, we subsequently synthesized a polymeric NP that could co-deliver MTDH-small interfering RNA (MTDH–siRNA) and TAX into the breast cancer tumors in tumor-bearing mice. The NPs were composed of a cationic copolymer, which wrapped TAX in the inside and adsorbed the negatively charged siRNA on their surface with high drug-loading efficiency and good stability. Conclusions NP-based co-delivery approach can effectively knock down the MTDH gene both in vitro and in vivo, which dramatically inhibits breast tumor growth, achieving effective TAX chemotherapy treatment without overt side effects. This study provides a potential therapeutic strategy for the treatment of a wide range of solid tumors highly expressing MTDH. 2018-10-01T15:47:45Z 2018-10-01T15:47:45Z 2018-09 2017-10 2018-09-23T03:32:15Z Article http://purl.org/eprint/type/JournalArticle 1465-542X http://hdl.handle.net/1721.1/118308 Yang, Liu et al. "Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro." Breast Cancer Research 20 (September 2018): 113 © 2018 The Authors https://orcid.org/0000-0001-8131-2468 https://orcid.org/0000-0003-0551-1208 en https://doi.org/10.1186/s13058-018-1042-7 Breast Cancer Research Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ The Author(s). application/pdf BioMed Central BioMed Central |
| spellingShingle | Yang, Liu Tian, Yanhua Leong, Wei Sun Song, Heng Yang, Wei Wang, Meiqi Wang, Xinle Kong, Jing Shan, Baoen Song, Zhengchuan Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title | Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title_full | Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title_fullStr | Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title_full_unstemmed | Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title_short | Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| title_sort | efficient and tumor specific knockdown of mtdh gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro |
| url | http://hdl.handle.net/1721.1/118308 https://orcid.org/0000-0001-8131-2468 https://orcid.org/0000-0003-0551-1208 |
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