Cell fate following irradiation of MDA-MB-231 and MCF-7 breast cancer cells pre-exposed to the setrahydroisoquinoline sulfamate microtubule disruptor STX3451

dc.contributor.authorHargrave, Scott Daniel
dc.contributor.authorJoubert, Anna Margaretha
dc.contributor.authorPotter, Barry V.L.
dc.contributor.authorDohle, Wolfgang
dc.contributor.authorMarais, Sumari
dc.contributor.authorMercier, Anne Elisabeth
dc.contributor.emailjoji.mercier@up.ac.zaen_US
dc.date.accessioned2023-09-21T09:25:30Z
dc.date.available2023-09-21T09:25:30Z
dc.date.issued2022-06-14
dc.descriptionThe compound STX3451 is not commercially available.en_US
dc.descriptionSUPPLEMENTARY MATERIAL : TABLE S1: Data analysis comparing flow cytometric quantification of individual cell cycle phases across 24-h and 48-h timelines. TABLE S2: Data analysis of flow cytometric quantification of the cell cycle distribution in MCF-7 cells exposed to STX3451 and radiation. TABLE S3: Statistical analysis of cell cycle distribution in MCF-7 cells exposed to STX3451 and radiation. TABLE S4: Data analysis comparing flow cytometric quantification of individual cell cycle phases across 24-h and 48-h timelines in MDA-MB-231 cells. TABLE S5: Statistical analysis of cell cycle progression in MDA-MB-231 cells exposed to STX3451 and radiation. TABLE S6: Statistical analysis of cell cycle distribution in MDA-MB-231 cells exposed to STX3451 and radiation. TABLE S7: Annexin-V analysis of MCF-7 cells 48-h. TABLE S8: Annexin-V statistical analysis of MDA-MB-231 48-h. TABLE S9: Colony formation in MCF-7 cells. TABLE S10: Colony formation in MDA-MB-231 cells. TABLE S11: The total number of Mn in MCF-7 cells that were terminated 2- and 24-h after radiation. TABLE S12: The total number of Mn in MDA-MB-231 cells terminated 2- and 24-h after radiation. TABLE S13: Number of Mn per cell in MCF-7 cells terminated 2-h after radiation. TABLE S14: Number of Mn per cell in MCF-7 cells terminated 24-h after radiation. TABLE S15: Number of Mn per cell in MDA-MB-231 cells terminated 2-h after radiation. TABLE S16: The number of Mn per cell in MDA-MB-231 cells that were terminated 24-h after radiation. TABLE S17: Superoxide detection in MCF-7 cells treated with the various modalities. TABLE S18: Superoxide detection in pre-sensitized MDA-MB-231 cells. TABLE S19: Statistical analysis of ATM expression in combination treated MCF-7 and MDA-MB-231 cells 2- and 24-h post-radiation. TABLE S20: Nontumored animal toxicity assay; VIDEO S1: not applicable.en_US
dc.description.abstractAtetrahydroisoquinoline (THIQ) core is able tomimic theAand 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 non-steroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radiation 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 findings 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.en_US
dc.description.departmentPhysiologyen_US
dc.description.librarianam2023en_US
dc.description.sponsorshipThe Research Committee of the University of Pretoria, the Struwig-Germeshuysen Trust, the Cancer Association of South Africa (CANSA), the National Research Foundation (NRF) and the Research Development Programme of the University of Pretoria (RDP-UP).en_US
dc.description.urihttps://www.mdpi.com/journal/moleculesen_US
dc.identifier.citationHargrave, S.D.; Joubert, A.M.; Potter, B.V.L.; Dohle, W.; Marais, S.; Mercier, A.E. Cell Fate following Irradiation of MDA-MB-231 and MCF-7 Breast Cancer Cells Pre-Exposed to the Tetrahydroisoquinoline Sulfamate Microtubule Disruptor STX3451. Molecules 2022, 27, 3819. https://DOI.org/10.3390/molecules27123819.en_US
dc.identifier.issn1420-3049 (online)
dc.identifier.other10.3390/molecules27123819
dc.identifier.urihttp://hdl.handle.net/2263/92371
dc.language.isoenen_US
dc.publisherMDPIen_US
dc.rights© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.en_US
dc.subjectCanceren_US
dc.subject2-Methoxyestradiolen_US
dc.subjectTetrahydroisoquinoline analog (STX3451)en_US
dc.subjectRadiosensitizationen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectApoptosisen_US
dc.subjectMicronucleien_US
dc.subjectDNA damage response (DDR)en_US
dc.subjectMicrotubule disrupting agent (MDA)en_US
dc.subjectRadiationen_US
dc.subjectSDG-03: Good health and well-beingen_US
dc.subjectAtetrahydroisoquinoline (THIQ)en_US
dc.titleCell fate following irradiation of MDA-MB-231 and MCF-7 breast cancer cells pre-exposed to the setrahydroisoquinoline sulfamate microtubule disruptor STX3451en_US
dc.typeArticleen_US

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