Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels
Fuente:
Wiley Open Access
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Artículo Open Access |
| Published: |
Wiley
2024
|
| Subjects: | |
| Online Access: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1867006516184219648 |
|---|---|
| author | Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen |
| author_facet | Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen |
| collection | Wiley Open Access |
| contents | Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen Chemical Biology & Drug Design AbstractTaxol (paclitaxel) is the first approved microtubule‐stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first‐line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer‐associated missence mutations in β‐tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol‐resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol‐resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug‐susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6‐fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 μM. 10.1111/cbdd.14513 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1111/cbdd.14513 |
| format | Artículo Open Access |
| id | wiley_oa_10_1111_cbdd_14513 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen Chemical Biology & Drug Design Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels Lihua Zhou Xi Ding Jingjing Cao Yu Feng Yuqin Gu Ling Liu Rong Chen Dongyun Gao Xiaoling Chen Chemical Biology & Drug Design AbstractTaxol (paclitaxel) is the first approved microtubule‐stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first‐line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer‐associated missence mutations in β‐tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol‐resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol‐resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug‐susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6‐fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 μM. 10.1111/cbdd.14513 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels |
| topic | Chemical Biology & Drug Design |
| url | https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14513 |