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

• DOI: 10.1101/2023.02.15.528599
• Publication Date: 2023-02-16T01:15:20Z
• 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 tumor

Abstract Background Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, 5-year survival rates stands at only 9%. Triptolides have potent anti-tumor activity against different types cancers, including pancreatic cancer, however poor solubility toxicity limit their translation into clinical use. Methods We synthesized a novel pro-drug triptolide, ( E )-19-[(1’-benzoyloxy-1’-phenyl)-methylidene]-Triptolide (CK21), formulated an emulsion for vitro vivo testing rats mice, using human cell lines patient-derived tumor organoids. A time-course transcriptomic profiling organoids treated with CK21 was conducted to define its mechanism action, as well single time point post-CK21 administration vivo. Findings Intravenous emulsified resulted stable release anti-proliferative effects on vitro, minimal . Time course revealed <10 differentially expressed genes (DEGs) 3 h ∼8,000 DEGs 12 h. 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. Interpretation triptolide that exerts tumors by inhibiting Funding The study efficacy supported part research grant from Cinkate Pharmaceutical Corp; funders had no role design, interpretation or decision publish. Patient-derived were generous gift Organoid Primary Culture Research Core University Chicago.