A novel triptolide analog downregulates NF-kB and induces mitochondrial apoptosis pathways in human pancreatic cancer
- University of Chicago, United States
- Cinkate Pharmaceutical Corp, China
- Indiana University, United States
Abstract
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, (E)-19-[(1'-benzoyloxy-1'-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and using 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 <10 differentially expressed genes (DEGs) at 3 h and ~8,000 DEGs at 12 h. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB 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. CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.
Data availability
Sequencing data have been deposited in GEO under Accession code GSE225011
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Triptolide analogs induced apoptosis on pancreatic cancer patient-derived organoidsNCBI Gene Expression Omnibus, GSE225011.
Article and author information
Author details
Funding
Cinkate Pharmaceutical Corp
- Anita S Chong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Wafik S El-Deiry, Brown University, United States
Ethics
Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee at the University of Chicago, and adhered to the standards of the NIH Guide for the Care and Use of Laboratory Animals. Pancreatic tumors from patients with pancreatic ductal adenocarcinoma were collected under University of Chicago IRB12-1108 and IRB13-1149.
Version history
- Received: December 29, 2022
- Preprint posted: February 15, 2023 (view preprint)
- Accepted: October 24, 2023
- Accepted Manuscript published: October 25, 2023 (version 1)
- Version of Record published: February 12, 2024 (version 2)
Copyright
© 2023, Tian et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A novel triptolide analog downregulates NF-kB and induces mitochondrial apoptosis pathways in human pancreatic cancer
eLife 12:e85862.
https://doi.org/10.7554/eLife.85862
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