A novel triptolide analog downregulates NF-kB and induces mitochondrial apoptosis pathways in human pancreatic cancer

  1. Qiaomu Tian
  2. Peng Zhang
  3. Yihan Wang
  4. Youhui Si
  5. Dengping Yin
  6. Christopher R Weber
  7. Melissa L Fishel
  8. Karen E Pollok
  9. Bo Qiu
  10. Fei Xiao
  11. Anita S Chong  Is a corresponding author
  1. University of Chicago, United States
  2. Cinkate Pharmaceutical Corp, China
  3. 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

The following data sets were generated

Article and author information

Author details

  1. Qiaomu Tian

    Department of Surgery, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4267-7362
  2. Peng Zhang

    Cinkate Pharmaceutical Corp, Shanghai, China
    Competing interests
    Peng Zhang, was an employee of Cinkate Pharmaceutical Corp. Is listed as an inventor on Patent WO2018/019301A1, which covers the design and use of CK21 for pancreatic cancer..
  3. Yihan Wang

    Department of Surgery, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Youhui Si

    Department of Surgery, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Dengping Yin

    Department of Surgery, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  6. Christopher R Weber

    Department of Pathology, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  7. Melissa L Fishel

    Department of Pediatrics, Indiana University, indianapolis, United States
    Competing interests
    No competing interests declared.
  8. Karen E Pollok

    Department of Pediatrics, Indiana University, indianapolis, United States
    Competing interests
    No competing interests declared.
  9. Bo Qiu

    Cinkate Pharmaceutical Corp, Shanghai, China
    Competing interests
    Bo Qiu, was an employee of Cinkate Pharmaceutical Corp..
  10. Fei Xiao

    Cinkate Pharmaceutical Corp, Shanghai, China
    Competing interests
    Fei Xiao, is listed as an inventor on Patent WO2018/019301A1, which covers the design and use of CK21 for pancreatic cancer..
  11. Anita S Chong

    Department of Surgery, University of Chicago, Chicago, United States
    For correspondence
    achong@uchicago.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0460-0196

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.

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.

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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  1. Qiaomu Tian
  2. Peng Zhang
  3. Yihan Wang
  4. Youhui Si
  5. Dengping Yin
  6. Christopher R Weber
  7. Melissa L Fishel
  8. Karen E Pollok
  9. Bo Qiu
  10. Fei Xiao
  11. Anita S Chong
(2023)
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

Share this article

https://doi.org/10.7554/eLife.85862

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