{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T10:59:19Z","timestamp":1778497159701,"version":"3.51.4"},"reference-count":91,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality of life in patients receiving standard treatment for metastatic prostate cancer. Methods: This phase II, double-blind, randomized controlled trial included 45 participants (aged 57\u201381 years) assigned to doxycycline (100 mg daily) or a placebo for six months. The primary outcome was the percentage change in PSA levels at 3 and 6 months. Secondary outcomes included quality of life (EQ-5D-5L), cognitive function (Mini-Mental State Examination), and glucose levels. Additionally, a structure\u2013activity relationship (SAR) analysis was performed through an extensive bibliographic review to identify pharmacophores responsible for doxycycline\u2019s biological activity, particularly its tetracyclic core. The SAR analysis included tetracyclines and derivatives, androgen-targeting agents, and other pharmacologically relevant molecules used in prostate cancer therapy. Statistical analysis was conducted using multivariate logistic regression. Results: At six months, the doxycycline group showed a median PSA reduction of 60% compared to 10% in the placebo group (p = 0.043). A \u226550% reduction in PSA levels was observed in 71.4% of patients receiving doxycycline versus 20.8% in the placebo group (p = 0.001), with an adjusted relative risk of 10.309 (95% CI: 2.359\u201345.055, p = 0.002). Quality of life improved, with 7.1% of doxycycline-treated patients reporting poor quality of life compared to 42.9% in the placebo group (p = 0.028). A slight improvement in cognitive function was also noted (p = 0.037). SAR analysis suggested that the tetracyclic ring of doxycycline may play a crucial role in its observed biological effects. Conclusions: Doxycycline demonstrates potential as an adjunctive therapy in metastatic prostate cancer by reducing PSA levels and improving quality of life. The SAR analysis supports the hypothesis that its tetracyclic structure may be responsible for its therapeutic effects. Further large-scale trials are warranted to confirm these findings.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040404","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Impact of Doxycycline as an Adjunctive Therapy on Prostate-Specific Antigen, Quality of Life, and Cognitive Function in Metastatic Prostate Cancer Patients: A Phase II Randomized Controlled Trial"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-0051","authenticated-orcid":false,"given":"Jos\u00e9","family":"Guzm\u00e1n-Esquivel","sequence":"first","affiliation":[{"name":"Clinical Epidemiology Research Unit, Mexican Institute of Social Security Institute, Villa de Alvarez, Colima 28984, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossana S.","family":"Garcia-Garcia","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology Research Unit, Mexican Institute of Social Security Institute, Villa de Alvarez, Colima 28984, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-3095","authenticated-orcid":false,"given":"Gustavo A.","family":"Hern\u00e1ndez-Fuentes","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, School of Medicine, University of Colima, Colima 28040, Mexico"},{"name":"State Cancerology Institute of Colima, Health Services of the Mexican Social Security Institute for Welfare (IMSS-BIENESTAR), Colima 28085, Mexico"},{"name":"Faculty of Chemical Sciences, University of Colima, Coquimatlan 28400, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-1895","authenticated-orcid":false,"given":"Jes\u00fas","family":"Venegas-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Mexican Institute of Social Security (IMSS), General Hospital of Zone No. 1, IMSS, Villa de Alvarez 28984, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos D.","family":"Barajas-Mej\u00eda","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology Research Unit, Mexican Institute of Social Security Institute, Villa de Alvarez, Colima 28984, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6307-1696","authenticated-orcid":false,"given":"Idalia","family":"Garza-Veloz","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory, Unidad de Medicina Humana y Ciencias de la Salud, Universidad Aut\u00f3noma de Zacatecas, Zacatecas 98160, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-9068","authenticated-orcid":false,"given":"Margarita L.","family":"Martinez-Fierro","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory, Unidad de Medicina Humana y Ciencias de la Salud, Universidad Aut\u00f3noma de Zacatecas, Zacatecas 98160, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7079-0752","authenticated-orcid":false,"given":"Nancy E.","family":"Maga\u00f1a-Vergara","sequence":"additional","affiliation":[{"name":"Faculty of Chemical Sciences, University of Colima, Coquimatlan 28400, Mexico"},{"name":"Consejo Nacional de Humanidades, Ciencia y Tecnolog\u00eda (CONAHCYT), Mexico City 03940, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 A.","family":"Guzm\u00e1n-Sol\u00f3rzano","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, School of Medicine, University of Colima, Colima 28040, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8432-0997","authenticated-orcid":false,"given":"Patricia","family":"Calvo-Soto","sequence":"additional","affiliation":[{"name":"Coordination of Planning and Institutional Liaison, IMSS OOAD Colima, Colima 28030, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar N.","family":"Avila-Zamora","sequence":"additional","affiliation":[{"name":"State Cancerology Institute of Colima, Health Services of the Mexican Social Security Institute for Welfare (IMSS-BIENESTAR), Colima 28085, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Fuentes-Murguia","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, School of Medicine, 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1007\/s11255-023-03653-7","article-title":"Regional and National Burden of Prostate Cancer: Incidence, Mortality, Years of Life Lost, and Disability-Adjusted Life Years, in Mexico and Latin America from 1990 to 2019","volume":"55","year":"2023","journal-title":"Int. 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