{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:14:32Z","timestamp":1760235272967,"version":"build-2065373602"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001325","name":"Cancer Association of South Africa","doi-asserted-by":"publisher","award":["AOV741","AOW228"],"award-info":[{"award-number":["AOV741","AOW228"]}],"id":[{"id":"10.13039\/501100001325","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The National Research Foundation","award":["NRF 105992, 90523, 85818"],"award-info":[{"award-number":["NRF 105992, 90523, 85818"]}]},{"name":"Struwig-Germeshuysen Trust","award":["AON074"],"award-info":[{"award-number":["AON074"]}]},{"name":"The School of Medicine Research Committee of the University of Pretoria (RESCOM)","award":["AOR984"],"award-info":[{"award-number":["AOR984"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>2-Ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) is an in silico-designed estradiol analogue which has improved the parent compound\u2019s efficacy in anti-cancer studies. In this proof-of-concept study, the potential radiosensitizing effects of ESE-16 were investigated in an in vitro deconstructed bone metastasis model. Prostate (DU 145) and breast (MDA-MB-231) tumor cells, osteoblastic (MC3T3-E1) and osteoclastic (RAW 264.7) bone cells and human umbilical vein endothelial cells (HUVECs) were representative components of such a lesion. Cells were exposed to a low-dose ESE-16 for 24 hours prior to radiation at non-lethal doses to determine early signaling and molecular responses of this combination treatment. Tartrate-resistant acid phosphatase activity and actin ring formation were investigated in osteoclasts, while cell cycle progression, reactive oxygen species generation and angiogenic protein expression were investigated in HUVECs. Increased cytotoxicity was evident in tumor and endothelial cells while bone cells appeared to be spared. Increased mitotic indices were calculated, and evidence of increased deoxyribonucleic acid damage with retarded repair, together with reduced metastatic signaling was observed in tumor cells. RAW 264.7 macrophages retained their ability to differentiate into osteoclasts. Anti-angiogenic effects were observed in HUVECs, and expression of hypoxia-inducible factor 1-\u03b1 was decreased. Through preferentially inducing tumor cell death and potentially inhibiting neovascularization whilst preserving bone physiology, this low-dose combination regimen warrants further investigation for its promising therapeutic application in bone metastases management, with the additional potential of limited treatment side effects.<\/jats:p>","DOI":"10.3390\/cells10082105","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T03:43:04Z","timestamp":1629171784000},"page":"2105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Intracellular Signaling Responses Induced by Radiation within an In Vitro Bone Metastasis Model after Pre-Treatment with an Estrone Analogue"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9657-9728","authenticated-orcid":false,"given":"Jolene","family":"Helena","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6931-7554","authenticated-orcid":false,"given":"Anna","family":"Joubert","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-7235","authenticated-orcid":false,"given":"Peace","family":"Mabeta","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Coetzee","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy","family":"Lakier","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Steve Biko Academic Hospital, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2030-9879","authenticated-orcid":false,"given":"Anne","family":"Mercier","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Maurizi, A., and Rucci, N. 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