{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:47:16Z","timestamp":1790207236055,"version":"4.1.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T00:00:00Z","timestamp":1714780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T00:00:00Z","timestamp":1714780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100013778","name":"Appendix Cancer Pseudomyxoma Peritonei Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013778","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["CA249087"],"award-info":[{"award-number":["CA249087"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["CA258692"],"award-info":[{"award-number":["CA258692"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mucpharm Pty Ltd"},{"DOI":"10.13039\/100007154","name":"Wake Forest University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007154","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Surg Oncol"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Introduction<\/jats:title>\n                <jats:p>Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Patients and Methods<\/jats:title>\n                <jats:p>PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37\u00a0\u00b0C and 42\u00a0\u00b0C with and without bromelain pretreatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12\/16, 75%) and high-grade AC (4\/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, <jats:italic>p<\/jats:italic>\u2009=\u20090.0009) or NAC alone (47% versus 12.8%, <jats:italic>p<\/jats:italic>\u2009=\u20090.0027). Bromelain demonstrated &gt; 31% organoid viability reduction at 60 min (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and &gt; 66% in 48 h (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (<jats:italic>p<\/jats:italic>\u2009=\u20090.0001) and 35.5% (<jats:italic>p<\/jats:italic>\u2009=\u20090.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3\/7 activity and decreased Bcl-2 (<jats:italic>p<\/jats:italic>\u2009=\u20090.009) and Bcl-xL (<jats:italic>p<\/jats:italic>\u2009=\u20090.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A\/B I (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.03) and II (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.031) were increased; while ATG7 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), ATG 12 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.04), and Becline 1(<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.03), expression decreased in bromelain-treated PTOs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1245\/s10434-024-15355-0","type":"journal-article","created":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T21:01:24Z","timestamp":1714856484000},"page":"5377-5389","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer"],"prefix":"10.1245","volume":"31","author":[{"given":"Nadeem","family":"Wajih","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Erali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven D.","family":"Forsythe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia R.","family":"Schaaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A.","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shay","family":"Soker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos I.","family":"Votanopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,4]]},"reference":[{"key":"15355_CR1","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1200\/JCO.2011.39.7166","volume":"30","author":"TC Chua","year":"2012","unstructured":"Chua TC, et al. 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Dr. Konstantinos Votanopoulos declares Organoid released patents. This research stems from the Wake Forest Organoids Research Center and was supported by the Wake Forest Institute for Regenerative Medicine, the Tumor Tissue and Pathology Shared Resource, Mucpharm Pty Ltd, and the Appendix Cancer Pseudomyxoma Peritonei Foundation (ACPMP). The other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure"}}]}}