{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:08:44Z","timestamp":1792804124074,"version":"4.5.0"},"reference-count":68,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"laboratory LR18ES03, the France\u2013Tunisia CMCU-Campus PHC-Utique","award":["22G0809\/47608VJ"],"award-info":[{"award-number":["22G0809\/47608VJ"]}]},{"name":"France\/PHC Utique","award":["24G0807\/50283RD"],"award-info":[{"award-number":["24G0807\/50283RD"]}]},{"name":"French Ministry of Europe and Foreign Affairs and the Tunisian Ministry of Higher Education and Scientific Research","id":[{"id":"https:\/\/ror.org\/05v1m8q81","id-type":"ROR","asserted-by":"crossref"}]},{"name":"University of Tunis El Manar and a France\u2013Tunisia exchange program","id":[{"id":"https:\/\/ror.org\/029cgt552","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Although cisplatin is widely used in chemotherapy, its clinical efficacy is often limited by adverse effects and resistance. Thus, natural bioactive compounds are gaining attention as complementary therapeutic agents. This study aimed to evaluate the anti-tumor effects of Annona muricata leaf extract on murine breast cancer 4T1 cells, used alone or in combination with cisplatin. Cisplatin induced intrinsic apoptosis through mitochondrial membrane disruption, up-regulation of the Bax gene and inhibition of the PI3K\/AKT\/mTOR signaling pathway. Cisplatin also promoted hypoxia by HIF1\u03b1 gene expression, inflammation by TNF\u03b1 and IL-6 gene expression, and induced cell cycle arrest at the sub-G1 phase by down-regulation of cyclin D1 and cyclin E1 genes. Annona muricata leaf extract triggered autophagy-mediated 4T1 cell death through mainly mTOR down-regulation and increased expression of Beclin1 and LC3 genes. It also induced cell cycle arrest at sub-G1 and S phases in a concentration- and time-dependent manner. When, combined with cisplatin, Annona muricata extract shifts the cell death pathway from intrinsic apoptosis toward autophagy by reduced caspase-3 gene expression and activity and enhanced LC3-I to LC3-II conversion. Moreover, Annona muricata extract attenuated cisplatin-induced inflammation by inhibiting TNF\u03b1 and IL-6 gene expression and reinforced cell cycle arrest through suppression of the cyclin D1 gene. In conclusion, our results suggest that Annona muricata leaf extract exerts significant anti-tumor activity in breast cancer cells and may enhance cisplatin efficacy by shifting the signaling pathway from intrinsic apoptosis toward autophagy, and attenuating inflammation-related effects, supporting its potential use as a complementary therapeutic strategy.<\/jats:p>","DOI":"10.3390\/cells15030213","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T13:55:34Z","timestamp":1769176534000},"page":"213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synergistic Anticancer Activity of Annona muricata Leaf Extract and Cisplatin in 4T1 Triple-Negative Breast Cancer Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Oumayma","family":"Kouki","sequence":"first","affiliation":[{"name":"LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Montassar","family":"Lasram","sequence":"additional","affiliation":[{"name":"LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel","family":"Abidi","sequence":"additional","affiliation":[{"name":"LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7814-9927","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Leprince","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8181-9445","authenticated-orcid":false,"given":"Imen","family":"Ghzaiel","sequence":"additional","affiliation":[{"name":"Clermont Auvergne National Polytechnic Institute, INP, French National Centre for Scientific Research, Institut Pascal, University Clermont Auvergne, 63001 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-129X","authenticated-orcid":false,"given":"John J.","family":"Mackrill","sequence":"additional","affiliation":[{"name":"Department of Physiology, University College Cork, Western Gateway Building, Western Road, T12 XF62 Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-0858","authenticated-orcid":false,"given":"Taoufik","family":"Ghrairi","sequence":"additional","affiliation":[{"name":"LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6330-0172","authenticated-orcid":false,"given":"G\u00e9rard","family":"Lizard","sequence":"additional","affiliation":[{"name":"Laboratoire Interdisciplinaire Carnot de Bourgogne ICB UMR 6303 (Team Prof. N. Millot), French National Center for Scientific Research (CNRS), Inserm, University Bourgogne Europe, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8062-6561","authenticated-orcid":false,"given":"Olfa","family":"Masmoudi-Kouki","sequence":"additional","affiliation":[{"name":"LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","unstructured":"(2024, December 24). WHO Breast Cancer. 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