Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor
Atetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties tha...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
MDPI
2022
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| _version_ | 1797107509118369792 |
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| author | Hargrave, SD Joubert, AM Potter, B Dohle, W Marais, S Mercier, AE |
| author_facet | Hargrave, SD Joubert, AM Potter, B Dohle, W Marais, S Mercier, AE |
| author_sort | Hargrave, SD |
| collection | OXFORD |
| description | Atetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2),
an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by sulfamoylation. The nonsteroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydro isoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radition biology. We investigated whether 24 h pre-treatment with STX3451 could pre-sensitize MCF-7 and MDA-MB-231 breast
cancer cells to radiation. This regimen showed a clear increase in cytotoxicity compared to the individual modalities, results that
were contiguous in spectrophotometric analysis, flow cytometric quantification of apoptosis induction, clonogenic studies and
microscopy techniques. Drug pre-treatment increased radiation-induced DNA damage, with statistically more double-strand (ds)
DNA breaks demonstrated. The latter could be due to the induction of a radiation-sensitive metaphase block or the increased
levels of reactive oxygen species, both evident after compound exposure. STX3451 pre -exposure may also delay DNA repair
mechanisms, as the DNA damage response element ataxia telangiectasia mutated (ATM) was depressed. These in vitro finding s
may translate into in vivo models, with the ultimate aim of reducing both radiation and drug doses for maximal clinical effect
with minimal adverse effects. |
| first_indexed | 2024-03-07T07:17:09Z |
| format | Journal article |
| id | oxford-uuid:a3914ca1-16f2-4f98-bfc3-fb1ce32af4b1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:17:09Z |
| publishDate | 2022 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:a3914ca1-16f2-4f98-bfc3-fb1ce32af4b12022-08-23T11:18:50ZCell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptorJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a3914ca1-16f2-4f98-bfc3-fb1ce32af4b1EnglishSymplectic ElementsMDPI2022Hargrave, SDJoubert, AMPotter, BDohle, WMarais, SMercier, AEAtetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by sulfamoylation. The nonsteroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydro isoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radition biology. We investigated whether 24 h pre-treatment with STX3451 could pre-sensitize MCF-7 and MDA-MB-231 breast cancer cells to radiation. This regimen showed a clear increase in cytotoxicity compared to the individual modalities, results that were contiguous in spectrophotometric analysis, flow cytometric quantification of apoptosis induction, clonogenic studies and microscopy techniques. Drug pre-treatment increased radiation-induced DNA damage, with statistically more double-strand (ds) DNA breaks demonstrated. The latter could be due to the induction of a radiation-sensitive metaphase block or the increased levels of reactive oxygen species, both evident after compound exposure. STX3451 pre -exposure may also delay DNA repair mechanisms, as the DNA damage response element ataxia telangiectasia mutated (ATM) was depressed. These in vitro finding s may translate into in vivo models, with the ultimate aim of reducing both radiation and drug doses for maximal clinical effect with minimal adverse effects. |
| spellingShingle | Hargrave, SD Joubert, AM Potter, B Dohle, W Marais, S Mercier, AE Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title | Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title_full | Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title_fullStr | Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title_full_unstemmed | Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title_short | Cell fate following irradiation of MDA-MB-231- and MCF-7 breast cancer cells pre-exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
| title_sort | cell fate following irradiation of mda mb 231 and mcf 7 breast cancer cells pre exposed to a tetrahydroisoquinoline sulfamate microtubule disruptor |
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