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

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

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CK21 pharmacokinetic in rats: detection of CK21 and Triptolide in male and female rats after IV injection (SD: standard deviation; ND: not detected; CV: coefficient of variation; BQL: below quantification limit)

CK21 viability assay with different cancer cell lines

Bioluminescence intensity of each mice bearing luciferase transfected AsPC-1 orthotopic tumors under 28 days treatment of CK21 (FD: found dead).

CK21 efficacy study on AsPC-1 and Panc-1 subcutaneous tumors (SEM: standard error).

* Size for AsPC-1 tumors and mice weight under different dosages for CK21
* Size for Panc-1 tumors and mice weight under 3 mg/kg dosage for CK21

CK21 efficacy study on AsPC-1 subcutaneous tumor with different treatment plans (SEM: standard error).

* Combo therapy
* Resue therapy
* ...