{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:10:59Z","timestamp":1785431459113,"version":"3.56.0"},"reference-count":88,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Sciences, Humanities, Technology and Innovation","award":["CF-2023-I-2755"],"award-info":[{"award-number":["CF-2023-I-2755"]}]},{"award":["CF-2023-I-2755"],"award-info":[{"award-number":["CF-2023-I-2755"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC50 values of 26.7 \u00b1 1.07 \u00b5M (Jurkat) and 30.5 \u00b1 1.54 \u00b5M (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC50 of 197.9 \u00b1 1.29 \u00b5M, corresponding to a 6.5\u20137.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy.<\/jats:p>","DOI":"10.3390\/ijms27146417","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of Darifenacin for T-Cell Acute Lymphoblastic Leukemia: Selective Targeting of the Non-Neuronal Cholinergic System and Lysosomal Cathepsins"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2332-4361","authenticated-orcid":false,"given":"Luis A.","family":"Flores-L\u00f3pez","sequence":"first","affiliation":[{"name":"SECIHTI-Laboratorio de Biomol\u00e9culas y Salud Infantil, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoalli","family":"Mart\u00ednez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Escuela de Medicina y Ciencias de la Salud, Tecnol\u00f3gico de Monterrey, Mexico City 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5654-8089","authenticated-orcid":false,"given":"Ignacio","family":"De la Mora-De la Mora","sequence":"additional","affiliation":[{"name":"Laboratorio de Biomol\u00e9culas y Salud Infantil, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-6739","authenticated-orcid":false,"given":"Gabriela","family":"L\u00f3pez-Herrera","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunodeficiencias, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2095-9182","authenticated-orcid":false,"given":"Sa\u00fal","family":"G\u00f3mez-Manzo","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioqu\u00edmica Gen\u00e9tica, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itzhel","family":"Garc\u00eda-Torres","sequence":"additional","affiliation":[{"name":"Laboratorio de Biomol\u00e9culas y Salud Infantil, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Hern\u00e1ndez-Ochoa","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Ciencias \u00d3micas y Epidemiolog\u00eda Microbiana, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Secretar\u00eda de Salud, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2058-5707","authenticated-orcid":false,"given":"Sergio","family":"Enr\u00edquez-Flores","sequence":"additional","affiliation":[{"name":"Laboratorio de Biomol\u00e9culas y Salud Infantil, Instituto Nacional de Pediatr\u00eda, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","first-page":"215","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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