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

• DOI: 10.7554/elife.85862
• Publication Date: 2023-10-25T11:20:05Z
• Authors: Qiaomu Tian; Peng Zhang; Yihan Wang; Youhui Si; Dengping Yin; Christopher R Weber; Melissa L Fishel; Karen E Pollok; Bo Qiu; Fei Xiao; Anita S Chong
• Keywords: Triptolide

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types cancers, including pancreatic cancer, however poor solubility toxicity limit their translation into clinical use. We synthesized a novel pro-drug triptolide, ( E )–19-[(1’-benzoyloxy-1’-phenyl)-methylidene]-Triptolide (CK21), which was formulated an emulsion for vitro vivo testing rats mice, used human cell lines patient-derived tumor organoids. A time-course transcriptomic profiling organoids treated with CK21 conducted to define its mechanism action, as well single time point post-CK21 administration vivo. Intravenous emulsified resulted stable release anti-proliferative effects on vitro, minimal Time course revealed <10 differentially expressed genes (DEGs) 3 hr ~8,000 DEGs 12 hr. Overall inhibition general RNA transcription observed, Ingenuity pathway analysis together functional cellular assays confirmed NF-κB pathway, increased oxidative phosphorylation mitochondrial dysfunction, ultimately reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, mitochondrial-mediated apoptosis. Thus, triptolide that exerts tumors by inhibiting