{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:45:09Z","timestamp":1761896709033,"version":"build-2065373602"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020851","name":"T\u00fcrkiye Burslar\u0131","doi-asserted-by":"publisher","award":["23AZ002939"],"award-info":[{"award-number":["23AZ002939"]}],"id":[{"id":"10.13039\/100020851","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with limited therapeutic options and frequent treatment-associated toxicities. L-asparaginase, a cornerstone in T-ALL therapy, is often restricted by hypersensitivity reactions and systemic side effects, highlighting the need for safer strategies to enhance its efficacy. This study investigated the potential of apigenin, a naturally occurring flavonoid with antioxidant and pro-apoptotic properties, to act as a chemosensitizer for L-asparaginase in MOLT-4 T-ALL cells. Cytotoxicity was assessed using the MTT assay, apoptosis by Annexin V\/PI staining, cell cycle distribution by flow cytometry, and mitochondrial membrane potential by JC-1 staining. Both apigenin and L-asparaginase produced dose- and time-dependent cytotoxicity, with combination treatment resulting in reduced IC\n                    <jats:sub>50<\/jats:sub>\n                    values. Apoptotic analysis showed significantly higher apoptosis in the combination-treated groups than in single-agent groups. Cell cycle analysis revealed that apigenin induced S-phase arrest and L-asparaginase induced G1-phase arrest, while the combination disrupted cell cycle progression at multiple checkpoints. JC-1 assay further demonstrated enhanced mitochondrial depolarization, with up to a 29.2-fold increase in cytoplasmic-to-mitochondrial fluorescence ratio in combination therapy compared to L-asparaginase alone. These findings indicate that apigenin potentiates L-asparaginase-induced cytotoxicity through mitochondrial dysfunction and intrinsic apoptotic signaling. The combined use of apigenin and L-asparaginase may provide a novel strategy to improve therapeutic efficacy in T-ALL while potentially reducing the toxicity associated with high-dose L-asparaginase monotherapy.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2025.1631505","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T06:24:59Z","timestamp":1761891899000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemosensitizing effect of apigenin on T-ALL cell therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Nigar","family":"Huseynova","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z\u00fcleyha","family":"Baran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rovshan","family":"Khalilov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afat","family":"Mammadova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuf","family":"Baran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13026","DOI":"10.1002\/jcb.28573","article-title":"Human bone marrow\u2010derived mesenchymal stromal cells in combination with silymarin regulate hepatocyte growth factor expression and genotoxicity in carbon tetrachloride induced hepatotoxicity in wistar rats","volume":"120","author":"Aithal","year":"2019","journal-title":"J. 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