{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:13:46Z","timestamp":1784632426197,"version":"3.55.0"},"reference-count":74,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018510","name":"Texas Woman's University","doi-asserted-by":"publisher","award":["REP grant"],"award-info":[{"award-number":["REP grant"]}],"id":[{"id":"10.13039\/100018510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. &amp; A. Gray (Euphorbiaceae), a plant native to the southern United States that has not been studied before. We investigated the antiproliferative activities and mechanisms of action of E. bicolor xylene extract in estrogen receptor-positive T47D and triple-negative MDA-MB-231 cell lines. The extract significantly reduced the viability of T47D and MDA-MB-231 cells in a dose-dependent manner. In MDA-MB-231 cells, the extract induced apoptosis via intracellular calcium overload, triggered by TRPV1 activation. This effect was diminished by the TRPV1 antagonist capsazepine and the calcium chelator BAPTA-AM. Intracellular calcium influx was confirmed through Fura-2 AM staining, revealing that E. bicolor phytochemicals activated TRPV1 in MDA-MB-231 cells. Treatment of T47D cells with E. bicolor xylene extract resulted in apoptosis associated with reactive oxygen species (ROS) generation (10-fold higher in T47D cells than in MDA-MB-231 cells) and mitochondrial calcium overload. These effects were significantly blocked when cells were pretreated with N-acetyl-l-cysteine (NAC), a ROS inhibitor. Both cell lines underwent apoptosis via multiple mitochondrial- and endoplasmic reticulum stress\u2013mediated pathways. This was supported by the activation of caspases 3, 8, and 9; increased expression of FAS, XBP1s, and CHOP; upregulation of BAX; and downregulation of BCL-2. In addition, PI3K, AKT, and pAKT protein expressions were also reduced in both cell lines, indicating downregulation of PI3K\/Akt signaling pathway. Phytochemicals in E. bicolor xylene extract could become promising ingredients for developing breast cancer therapeutics.<\/jats:p>","DOI":"10.3390\/ijms27020962","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Euphorbia bicolor Xylene Extract Induces Mitochondrial and Endoplasmic Reticulum Stress-Mediated Apoptotic Pathways in MDA-MB-231 and T47D Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Mafia Mahabub","family":"Rumpa","sequence":"first","affiliation":[{"name":"Division of Biology, School of the Sciences, Texas Woman\u2019s University, Denton, TX 76204, USA"},{"name":"Department of Breast Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Linh","family":"Ngo","sequence":"additional","affiliation":[{"name":"Division of Biology, School of the Sciences, Texas Woman\u2019s University, Denton, TX 76204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7389-6678","authenticated-orcid":false,"given":"Camelia","family":"Maier","sequence":"additional","affiliation":[{"name":"Division of Biology, School of the Sciences, Texas Woman\u2019s University, Denton, TX 76204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global patterns and trends in breast cancer incidence and mortality across 185 countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. 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