{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:29:02Z","timestamp":1792808942513,"version":"4.5.0"},"reference-count":64,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cinkate Pharmaceutical Corp","id":[{"id":"https:\/\/ror.org\/02sccna04","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,24]]},"abstract":"<jats:p>\n                    Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (\n                    <jats:italic>E<\/jats:italic>\n                    )\u201319-[(1\u2019-benzoyloxy-1\u2019-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed &lt;10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-\u03baB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-\u03baB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.\n                  <\/jats:p>","DOI":"10.7554\/elife.85862","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T07:20:05Z","timestamp":1698218405000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.85862","source":"Crossref","is-referenced-by-count":29,"title":["A novel triptolide analog downregulates NF-\u03baB and induces mitochondrial apoptosis pathways in human pancreatic cancer"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-7362","authenticated-orcid":true,"given":"Qiaomu","family":"Tian","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Surgery, The University of 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