{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T19:16:50Z","timestamp":1769541410183,"version":"3.49.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009045","name":"Uniwersytet Jagiello\u0144ski Collegium Medicum","doi-asserted-by":"publisher","award":["N42\/DBS\/000451"],"award-info":[{"award-number":["N42\/DBS\/000451"]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nat Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Castration-resistant prostate cancer\u00a0(CRPC) continues to represent a critical therapeutic hurdle owing to its resistance to both androgen deprivation and next-generation antiandrogens like abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from\n                    <jats:italic>Vitex agnus-castus<\/jats:italic>\n                    , was identified as a potent inhibitor of AKR1C3. CAS showed potent inhibitory activity in enzymatic assays (IC\u2085\u2080 = 5.99 \u00b5M), significantly suppressed AKR1C3-mediated coumberone metabolism in 22Rv1 prostate cancer cells, and showed greater cytotoxicity in AKR1C3-expressing 22Rv1 cells relative to AKR1C3-deficient LNCaP cells. CAS significantly enhanced ABI\u2019s cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31\u20130.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. CAS enhanced apoptosis in ABI-treated 22Rv1 cells, as well as combination showed only a limited effect against normal epithelial PNT-2 cell line. Docking and molecular dynamics simulations indicated a stable CAS\u2013AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11418-025-01974-8","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T20:14:24Z","timestamp":1765397664000},"page":"119-129","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer"],"prefix":"10.1007","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-9991","authenticated-orcid":false,"given":"Kamil","family":"Piska","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Zubek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Bucki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"\u015awitalska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Koczurkiewicz-Adamczyk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedykt","family":"W\u0142adyka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Ko\u0142aczkowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u017cbieta","family":"P\u0119kala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"1974_CR1","doi-asserted-by":"publisher","unstructured":"Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S Prostate cancer review: Genetics, Diagnosis, treatment Options, and alternative approaches. Molecules 2022;27. https:\/\/doi.org\/10.3390\/molecules27175730","DOI":"10.3390\/molecules27175730"},{"key":"1974_CR2","doi-asserted-by":"publisher","unstructured":"Le TK, Duong QH, Baylot V, Fargette C, Baboudjian M, Colleaux L et al (2023) Castration-Resistant prostate cancer: from uncovered resistance mechanisms to current treatments. Cancers (Basel) 15. https:\/\/doi.org\/10.3390\/cancers15205047","DOI":"10.3390\/cancers15205047"},{"key":"1974_CR3","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41419-022-05490-5","volume":"13","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Wei W, Li C, Yan S, Wang S, Xiao S et al (2022) Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein. Cell Death Dis 13:1034. https:\/\/doi.org\/10.1038\/s41419-022-05490-5","journal-title":"Cell Death Dis"},{"key":"1974_CR4","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1124\/dmd.108.022251","volume":"36","author":"N Kassner","year":"2008","unstructured":"Kassner N, Huse K, Martin HJ, G\u00f6dtel-Armbrust U, Metzger A, Meineke I et al (2008) Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos 36:2113\u20132120. https:\/\/doi.org\/10.1124\/dmd.108.022251","journal-title":"Drug Metab Dispos"},{"key":"1974_CR5","doi-asserted-by":"publisher","first-page":"1378292","DOI":"10.3389\/fphar.2024.1378292","volume":"15","author":"M Li","year":"2024","unstructured":"Li M, Zhang L, Yu J, Wang X, Cheng L, Ma Z et al (2024) AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies. Front Pharmacol 15:1378292. https:\/\/doi.org\/10.3389\/fphar.2024.1378292","journal-title":"Front Pharmacol"},{"key":"1974_CR6","doi-asserted-by":"publisher","first-page":"5613","DOI":"10.1158\/1078-0432.CCR-13-1151","volume":"19","author":"M Yepuru","year":"2013","unstructured":"Yepuru M, Wu Z, Kulkarni A, Yin F, Barrett CM, Kim J et al (2013) Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clin Cancer Res Off J Am Assoc Cancer Res 19:5613\u20135625. https:\/\/doi.org\/10.1158\/1078-0432.CCR-13-1151","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"1974_CR7","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1158\/1535-7163.MCT-18-1322","volume":"18","author":"C Liu","year":"2019","unstructured":"Liu C, Yang JC, Armstrong CM, Lou W, Liu L, Qiu X et al (2019) AKR1C3 promotes AR-V7 protein stabilization and confers resistance to AR-Targeted therapies in advanced prostate cancer. Mol Cancer Ther 18:1875\u20131886. https:\/\/doi.org\/10.1158\/1535-7163.MCT-18-1322","journal-title":"Mol Cancer Ther"},{"key":"1974_CR8","doi-asserted-by":"publisher","first-page":"102727","DOI":"10.1016\/j.eucr.2024.102727","volume":"54","author":"T Yoshizawa","year":"2024","unstructured":"Yoshizawa T, Nakanishi Y, Obinata D, Yamaguchi K, Masuda S, Takahashi S (2024) AKR1C3-negative high-risk metastatic castration-sensitive prostate cancer has long-term response to first-line treatment with abiraterone: four case reports. Urol Case Rep 54:102727. https:\/\/doi.org\/10.1016\/j.eucr.2024.102727","journal-title":"Urol Case Rep"},{"key":"1974_CR9","doi-asserted-by":"publisher","unstructured":"Cui X, Li C, Ding J, Yao Z, Zhao T, Guo J et al (2023) Establishing a Proteomics-Based signature of AKR1C3-Related genes for predicting the prognosis of prostate cancer. Int J Mol Sci 24. https:\/\/doi.org\/10.3390\/ijms24054513","DOI":"10.3390\/ijms24054513"},{"key":"1974_CR10","doi-asserted-by":"publisher","first-page":"11305","DOI":"10.1021\/acs.jmedchem.9b02138","volume":"63","author":"Y Liu","year":"2020","unstructured":"Liu Y, He S, Chen Y, Liu Y, Feng F, Liu W et al (2020) Overview of AKR1C3: inhibitor achievements and disease insights. J Med Chem 63:11305\u201311329. https:\/\/doi.org\/10.1021\/acs.jmedchem.9b02138","journal-title":"J Med Chem"},{"key":"1974_CR11","doi-asserted-by":"publisher","unstructured":"Yu X, Yan J, Li Y, Cheng J, Zheng L, Fu T et al (2023) Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3. Food Nutr Res 67. https:\/\/doi.org\/10.29219\/fnr.v67.9024","DOI":"10.29219\/fnr.v67.9024"},{"key":"1974_CR12","doi-asserted-by":"publisher","first-page":"110654","DOI":"10.1016\/j.cbi.2023.110654","volume":"385","author":"H Liu","year":"2023","unstructured":"Liu H, Yao Z, Sun M, Zhang C, Huang Y, Luo H et al (2023) Inhibition of AKR1Cs by Liquiritigenin and the structural basis. Chem Biol Interact 385:110654. https:\/\/doi.org\/10.1016\/j.cbi.2023.110654","journal-title":"Chem Biol Interact"},{"key":"1974_CR13","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.cbi.2008.10.015","volume":"178","author":"L Skarydov\u00e1","year":"2009","unstructured":"Skarydov\u00e1 L, Zivn\u00e1 L, Xiong G, Maser E, Ws\u00f3l V (2009) AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chem Biol Interact 178:138\u2013144. https:\/\/doi.org\/10.1016\/j.cbi.2008.10.015","journal-title":"Chem Biol Interact"},{"key":"1974_CR14","doi-asserted-by":"publisher","unstructured":"Carbone K, Gervasi F, Kozhamzharova L, Altybaeva N, S\u00f6nmez G\u00fcrer E, Sharifi-Rad J et al (2023) Casticin as potential anticancer agent: recent advancements in multi-mechanistic approaches. Front Mol Biosci 10. https:\/\/doi.org\/10.3389\/fmolb.2023.1157558","DOI":"10.3389\/fmolb.2023.1157558"},{"key":"1974_CR15","doi-asserted-by":"publisher","unstructured":"Souto EB, Durazzo A, Nazhand A, Lucarini M, Zaccardelli M, Souto SB et al Vitex agnus-castus L.: main features and nutraceutical perspectives. Forests 2020;11. https:\/\/doi.org\/10.3390\/f11070761","DOI":"10.3390\/f11070761"},{"key":"1974_CR16","doi-asserted-by":"publisher","unstructured":"Saul S Effects of vitex Agnes Castus on hormonal imbalances in polycystic ovary syndrome. Int J Basic Clin Pharmacol 2017;6:2051. https:\/\/doi.org\/10.18203\/2319-2003.ijbcp20173295","DOI":"10.18203\/2319-2003.ijbcp20173295"},{"key":"1974_CR17","first-page":"239","volume":"23","author":"M Mohammadi","year":"2019","unstructured":"Mohammadi M, Ramezani Tehrani F, Ziaei S, Gholami M, Azizi F (2019) Effect of *Vitex agnus-castus* fruits hydroalcoholic extract on sex hormones in rat with induced polycystic ovary syndrome (PCOS). Physiol Pharmacol 23:239\u2013246","journal-title":"Physiol Pharmacol"},{"key":"1974_CR18","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.jpba.2011.11.006","volume":"61","author":"J Xu","year":"2012","unstructured":"Xu J, Zhang Q, Zhao L, Wang Y, Xue L, Han T et al (2012) Quantitative determination and Pharmacokinetic study of casticin in rat plasma by liquid chromatography-mass spectrometry. J Pharm Biomed Anal 61:242\u2013246. https:\/\/doi.org\/10.1016\/j.jpba.2011.11.006","journal-title":"J Pharm Biomed Anal"},{"key":"1974_CR19","doi-asserted-by":"publisher","first-page":"3492","DOI":"10.1016\/j.bmcl.2012.03.085","volume":"22","author":"M Chen","year":"2012","unstructured":"Chen M, Adeniji AO, Twenter BM, Winkler JD, Christianson DW, Penning TM (2012) Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. Bioorg Med Chem Lett 22:3492\u20133497. https:\/\/doi.org\/10.1016\/j.bmcl.2012.03.085","journal-title":"Bioorg Med Chem Lett"},{"key":"1974_CR20","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1039\/D2MD00387B","volume":"14","author":"MA Marinovi\u0107","year":"2023","unstructured":"Marinovi\u0107 MA, Beki\u0107 SS, Kugler M, Brynda J, \u0160kerlov\u00e1 J, \u0160kori\u0107 D\u0110 et al (2023) X-ray structure of human aldo\u2013keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation{,} molecular Docking and structural analysis. RSC Med Chem 14:341\u2013355. https:\/\/doi.org\/10.1039\/D2MD00387B","journal-title":"RSC Med Chem"},{"key":"1974_CR21","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1158\/1535-7163.MCT-17-1023","volume":"17","author":"K Verma","year":"2018","unstructured":"Verma K, Gupta N, Zang T, Wangtrakluldee P, Srivastava SK, Penning TM et al (2018) AKR1C3 inhibitor KV-37 exhibits antineoplastic effects and potentiates enzalutamide in combination therapy in prostate adenocarcinoma cells. Mol Cancer Ther 17:1833\u20131845. https:\/\/doi.org\/10.1158\/1535-7163.MCT-17-1023","journal-title":"Mol Cancer Ther"},{"key":"1974_CR22","doi-asserted-by":"publisher","first-page":"12032","DOI":"10.1111\/jcmm.15831","volume":"24","author":"B Wang","year":"2020","unstructured":"Wang B, Wu S, Fang Y, Sun G, He D, Hsieh J-T et al (2020) The AKR1C3\/AR-V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression. J Cell Mol Med 24:12032\u201312043. https:\/\/doi.org\/10.1111\/jcmm.15831","journal-title":"J Cell Mol Med"},{"key":"1974_CR23","doi-asserted-by":"publisher","first-page":"e12902","DOI":"10.1111\/jfbc.12902","volume":"43","author":"C-C Lin","year":"2019","unstructured":"Lin C-C, Chen K-B, Tsai C-H, Tsai F-J, Huang C-Y, Tang C-H et al (2019) Casticin inhibits human prostate cancer DU 145 cell migration and invasion via Ras\/Akt\/NF-\u03baB signaling pathways. J Food Biochem 43:e12902. https:\/\/doi.org\/10.1111\/jfbc.12902","journal-title":"J Food Biochem"},{"key":"1974_CR24","doi-asserted-by":"publisher","first-page":"6369","DOI":"10.7314\/apjcp.2012.13.12.6369","volume":"13","author":"F-M Meng","year":"2012","unstructured":"Meng F-M, Yang J-B, Yang C-H, Jiang Y, Zhou Y-F, Yu B et al (2012) Vitexicarpin induces apoptosis in human prostate carcinoma PC-3 cells through G2\/M phase arrest. Asian Pac J Cancer Prev 13:6369\u20136374. https:\/\/doi.org\/10.7314\/apjcp.2012.13.12.6369","journal-title":"Asian Pac J Cancer Prev"},{"key":"1974_CR25","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1055\/s-2005-871235","volume":"71","author":"M Weisskopf","year":"2005","unstructured":"Weisskopf M, Schaffner W, Jundt G, Sulser T, Wyler S, Tullberg-Reinert H (2005) A vitex agnus-castus extract inhibits cell growth and induces apoptosis in prostate epithelial cell lines. Planta Med 71:910\u2013916. https:\/\/doi.org\/10.1055\/s-2005-871235","journal-title":"Planta Med"},{"key":"1974_CR26","doi-asserted-by":"publisher","first-page":"133","DOI":"10.7324\/JAPS.2017.71219","volume":"7","author":"AY Ibrahim","year":"2017","unstructured":"Ibrahim AY, El-Newary SA, Youness ER, Ibrahim AMM, El Kashak WA (2017) Protective and therapeutic effect of vitex agnus-castus against prostate cancer in rat. J Appl Pharm Sci 7:133\u2013143. https:\/\/doi.org\/10.7324\/JAPS.2017.71219","journal-title":"J Appl Pharm Sci"},{"key":"1974_CR27","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou TC (2010) Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res 70:440\u2013446. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1947","journal-title":"Cancer Res"},{"key":"1974_CR28","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1158\/1535-7163.MCT-16-0186","volume":"16","author":"C Liu","year":"2017","unstructured":"Liu C, Armstrong CM, Lou W, Lombard A, Evans CP, Gao AC (2017) Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol Cancer Ther 16:35\u201344. https:\/\/doi.org\/10.1158\/1535-7163.MCT-16-0186","journal-title":"Mol Cancer Ther"},{"key":"1974_CR29","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/pros.24118","volume":"81","author":"LS Graham","year":"2021","unstructured":"Graham LS, True LD, Gulati R, Schade GR, Wright J, Grivas P et al (2021) Targeting backdoor androgen synthesis through AKR1C3 inhibition: a presurgical hormonal ablative neoadjuvant trial in high-risk localized prostate cancer. Prostate 81:418\u2013426. https:\/\/doi.org\/10.1002\/pros.24118","journal-title":"Prostate"},{"key":"1974_CR30","doi-asserted-by":"publisher","first-page":"116193","DOI":"10.1016\/j.ejmech.2024.116193","volume":"268","author":"AC Pippione","year":"2024","unstructured":"Pippione AC, Kovachka S, Vigato C, Bertarini L, Mannella I, Sainas S et al (2024) Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer. Eur J Med Chem 268:116193. https:\/\/doi.org\/10.1016\/j.ejmech.2024.116193","journal-title":"Eur J Med Chem"},{"key":"1974_CR31","doi-asserted-by":"publisher","first-page":"114366","DOI":"10.1016\/j.ejmech.2022.114366","volume":"237","author":"AC Pippione","year":"2022","unstructured":"Pippione AC, Kilic-Kurt Z, Kovachka S, Sainas S, Rolando B, Denasio E et al (2022) New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold. Eur J Med Chem 237:114366. https:\/\/doi.org\/10.1016\/j.ejmech.2022.114366","journal-title":"Eur J Med Chem"},{"key":"1974_CR32","doi-asserted-by":"publisher","first-page":"10396","DOI":"10.1021\/acs.jmedchem.0c00939","volume":"63","author":"S Endo","year":"2020","unstructured":"Endo S, Oguri H, Segawa J, Kawai M, Hu D, Xia S et al (2020) Development of novel AKR1C3 inhibitors as new potential treatment for Castration-Resistant prostate cancer. J Med Chem 63:10396\u201310411. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c00939","journal-title":"J Med Chem"}],"container-title":["Journal of Natural Medicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11418-025-01974-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11418-025-01974-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11418-025-01974-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:39:47Z","timestamp":1769495987000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11418-025-01974-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["1974"],"URL":"https:\/\/doi.org\/10.1007\/s11418-025-01974-8","relation":{},"ISSN":["1340-3443","1861-0293"],"issn-type":[{"value":"1340-3443","type":"print"},{"value":"1861-0293","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]},"assertion":[{"value":"29 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study used commercially available human-derived cell lines (22Rv1 and LNCaP) that do not require ethical approval according to the institutional guidelines. All experimental procedures were conducted in accordance with relevant institutional and international regulations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}]}}