{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T13:19:25Z","timestamp":1775135965421,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Center grant for the Comprehensive Health Research Centre","award":["UID\/04923"],"award-info":[{"award-number":["UID\/04923"]}]},{"name":"Portuguese Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia\u2014FCT","award":["UID\/04923"],"award-info":[{"award-number":["UID\/04923"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Drug resistance (DR) is a major challenge in cancer therapy, contributing to approximately 90% of cancer-related deaths. While alterations in drug metabolism are known to be key drivers of DR, their role\u2014particularly in the early stages of acquired chemoresistance\u2014remains understudied. Phase I drug-metabolizing enzymes (DMEs), especially cytochrome P450s (CYPs), significantly influence the metabolic fate of chemotherapeutic agents, directly affecting drug response. This study aimed to investigate the role of Phase I DMEs in the early metabolic adaptation of breast cancer (BC) MCF-7 cells to doxorubicin (DOX). Methods: Four types of spheroids were generated from MCF-7 cells that were either DOX-sensitive (DOXS) or adapted to low concentrations of the chemotherapeutic agent (DOXA 25, 35, and 45 nM). The expression levels of 92 Phase I DMEs and the activities of specific CYP isoforms were assessed in both DOXS and DOXA spheroids. Results: A total of twenty-four DMEs, including fifteen CYPs and nine oxidoreductases, were found to be differentially expressed in DOXA spheroids. Pathway analysis identified key roles for the differentially expressed DMEs in physiologically relevant pathways, including the metabolism of drugs, arachidonic acid, retinoic acid, and vitamin D. Conclusions: The deconvolution of these pathways highlights a highly dynamic process driving early-stage DOX resistance, with a prominent role of CYP3A-dependent metabolism in DOX adaptation. Our findings provide valuable insights into the underlying molecular mechanisms driving the early adaptation of MCF-7 cells to DOX exposure.<\/jats:p>","DOI":"10.3390\/metabo15020136","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T03:47:06Z","timestamp":1739850426000},"page":"136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Adaptation of MCF-7 Breast Cancer Spheroids to the Chemotherapeutic Doxorubicin: The Dynamic Role of Phase I Drug Metabolizing Enzymes"],"prefix":"10.3390","volume":"15","author":[{"given":"Daniel","family":"Crispim","sequence":"first","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]},{"given":"Carolina","family":"Ramos","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-1313","authenticated-orcid":false,"given":"Francisco","family":"Esteves","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Instituto Polit\u00e9cnico de Set\u00fabal (IPS), Escola Superior de Sa\u00fade (ESS), Departamento de Ci\u00eancias Biom\u00e9dicas, Estefanilha, 2910-761 Set\u00fabal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-0076","authenticated-orcid":false,"given":"Michel","family":"Kranendonk","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"ref_1","unstructured":"Global Cancer Observatory (2024, October 12). 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