{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T22:58:56Z","timestamp":1781218736310,"version":"3.54.1"},"reference-count":26,"publisher":"Georg Thieme Verlag KG","issue":"07","funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["P20 GM130456"],"award-info":[{"award-number":["P20 GM130456"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"crossref","award":["2023-38821-39584"],"award-info":[{"award-number":["2023-38821-39584"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R37 AI052218"],"award-info":[{"award-number":["R37 AI052218"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["UL1TR000117"],"award-info":[{"award-number":["UL1TR000117"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["UL1TR001998"],"award-info":[{"award-number":["UL1TR001998"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004748","name":"Mashhad University of Medical Sciences","doi-asserted-by":"crossref","award":["4001118"],"award-info":[{"award-number":["4001118"]}],"id":[{"id":"10.13039\/501100004748","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Planta Med"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The efficacy of breast cancer chemotherapies is frequently limited by multidrug resistance (MDR), partly through efflux by ABC transporters, including ABCG2. This study evaluated whether phaeosphaeride A (PPA), a fungal metabolite isolated from a Paraphoma sp. endophyte of Ferula xylorhachis, can modulate ABCG2-mediated resistance to mitoxantrone (MTX). The endophyte was cultured and extracted with ethyl acetate, and the extract was purified by column chromatography and HPLC to yield PPA, whose structure was confirmed by NMR and MS analyses. Cytotoxicity of MTX, PPA, and their combination was assessed in MCF-7- and ABCG2-overexpressing MCF-7\/MX cells. MTX showed marked differential cytotoxicity (IC50\u2009=\u20091.6\u2009\u00b5M, 95% CI: 1.4\u200a\u2013\u200a1.9 in MCF-7 vs. &gt;\u200925\u2009\u00b5M in MCF-7\/MX; p\u2009&lt;\u20090.0001), whereas PPA exhibited comparable activity in both lines (23.2\u2009\u00b5M, 95% CI: 18.0\u200a\u2013\u200a30.1 vs. 36.1\u2009\u00b5M, 95% CI: 28.7\u200a\u2013\u200a46.0; p\u2009=\u20090.01). Co-treatment with PPA IC50\n          significantly reduced MTX IC50 to 0.4\u2009\u00b5M (95% CI: 0.3\u200a\u2013\u200a0.6) in MCF-7 and 1.9\u2009\u00b5M (95% CI: 1.2\u200a\u2013\u200a2.7) in MCF-7\/MX, restoring MTX sensitivity in resistant cells to near MCF-7 levels. Flow cytometry showed that PPA (IC50) increased intracellular MTX accumulation with stronger effects in MCF-7\/MX cells (p\u2009&lt;\u20090.0001) than in MCF-7 (p\u2009&lt;\u20090.05). In combination with MTX, PPA (IC50) increased Sub-G1 apoptotic populations in both lines.<\/jats:p>\n                  <jats:p>These findings demonstrate that PPA is unlikely to be a substrate of ABCG2 but functionally inhibits ABCG2-mediated efflux, contributing to the restoration of MTX sensitivity, although there may be additional mechanisms involved. PPA could be a promising MDR-reversal agent in ABCG2-driven chemotherapy resistance.<\/jats:p>","DOI":"10.1055\/a-2805-4670","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T23:55:56Z","timestamp":1770249356000},"page":"746-755","source":"Crossref","is-referenced-by-count":0,"title":["Phaeosphaeride A Isolated from an Endophytic Paraphoma sp. Alleviates ABCG2-mediated Resistance to Mitoxantrone in Breast Cancer Cells"],"prefix":"10.1055","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9044-4371","authenticated-orcid":false,"given":"Alireza","family":"Tavakkoli","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hojjat","family":"Mortazavi","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Iranshahi","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Kalalinia","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran"},{"name":"Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadijeh","family":"Jamialahmadi","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon S.","family":"Thorson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA"},{"name":"Center for Pharmaceutical Research and Innovation (CPRI), College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-4942","authenticated-orcid":false,"given":"Khaled A.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA"},{"name":"Center for Pharmaceutical Research and Innovation (CPRI), College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Mosaffa","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran"},{"name":"Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/S0140-6736(20)32381-3","article-title":"Breast cancer","volume":"397","author":"S Loibl","year":"2021","journal-title":"Lancet"},{"key":"ref2","first-page":"477","article-title":"Breast cancer statistics 2024","volume":"74","author":"A N Giaquinto","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1016\/S0140-6736(16)31891-8","article-title":"Breast cancer","volume":"389","author":"N Harbeck","year":"2017","journal-title":"Lancet"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"101205","DOI":"10.1016\/j.mam.2023.101205","article-title":"Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming","volume":"93","author":"R Mattioli","year":"2023","journal-title":"Mol Aspects Med"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/S0140-6736(23)00285-4","article-title":"Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: A patient-level meta-analysis of 100000 women from 86 randomised trials","volume":"401","author":"J Braybrooke","year":"2023","journal-title":"Lancet"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/med.21364","article-title":"Mitoxantrone, more than just another topoisomerase II poison","volume":"36","author":"B J Evison","year":"2016","journal-title":"Med Res Rev"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s10637-021-01182-7","article-title":"Efficacy and safety of mitoxantrone hydrochloride liposome injection in Chinese patients with advanced breast cancer: a randomized, open-label, active-controlled, single-center, phase II clinical trial","volume":"40","author":"L Wang","year":"2022","journal-title":"Invest New Drugs"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"6550","DOI":"10.21037\/tcr-24-1129","article-title":"Targeting breast cancer resistance protein (BCRP\/ABCG2) in cancer","volume":"13","author":"R Chen","year":"2024","journal-title":"Transl Cancer Res"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.addr.2008.07.003","article-title":"Functions of the breast cancer resistance protein (BCRP\/ABCG2) in chemotherapy","volume":"61","author":"K Noguchi","year":"2009","journal-title":"Adv Drug Del Rev"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"117486","DOI":"10.1016\/j.bmc.2023.117486","article-title":"The mechanisms of multidrug resistance of breast cancer and research progress on related reversal agents","volume":"95","author":"S Yu","year":"2023","journal-title":"Biorg Med Chem"},{"key":"ref11","first-page":"67","volume-title":"Chapter 3 \u2013 Efflux transporters in cancer resistance: Molecular and functional characterization of breast cancer resistance protein","author":"G An","year":"2020"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"8777","DOI":"10.1007\/s11033-022-07727-0","article-title":"Apigenin alleviates resistance to doxorubicin in breast cancer cells by acting on the JAK\/STAT signaling pathway","volume":"49","author":"M S Maashi","year":"2022","journal-title":"Mol Biol Rep"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1093\/jpp\/rgaa032","article-title":"Glucosamine attenuates drug resistance in Mitoxantrone-resistance breast cancer cells","volume":"73","author":"F Valinezhad Sani","year":"2021","journal-title":"J Pharm Pharmacol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.fct.2017.03.024","article-title":"Resveratrol as MDR reversion molecule in breast cancer: An overview","volume":"103","author":"N S 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Development and assessment of universal primers for potential secondary fungal DNA barcodes","volume":"35","author":"J B Stielow","year":"2015","journal-title":"Persoonia"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.simyco.2014.09.001","article-title":"Identification and nomenclature of the genus Penicillium","volume":"78","author":"C M Visagie","year":"2014","journal-title":"Stud Mycol"}],"container-title":["Planta Medica"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2805-4670.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T22:30:51Z","timestamp":1781217051000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2805-4670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":26,"journal-issue":{"issue":"07","published-online":{"date-parts":[[2026,6,11]]},"published-print":{"date-parts":[[2026,6]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2805-4670","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0032-0943","1439-0221"],"issn-type":[{"value":"0032-0943","type":"print"},{"value":"1439-0221","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,2,4]]},"published":{"date-parts":[[2026,2,4]]}}}