14-o-phosphonooxymethyltriptolide and Carcinoma--Pancreatic-Ductal

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGFβ signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGFβ. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.

Topics: Animals; Apoptosis; Cancer-Associated Fibroblasts; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Proliferation; Disease Models, Animal; Diterpenes; Epithelial Cells; Epoxy Compounds; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred C57BL; Mutation; Organophosphates; Pancreatic Neoplasms; Phenanthrenes; Proto-Oncogene Proteins p21(ras); Signal Transduction; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease hallmarked by limited patient survival. Resistance to chemotherapy, a major cause of treatment failure in PDAC patients, is often attributed to Cancer Stem Cells (CSCs). Pancreatic CSCs are a small subset of quiescent cells within a tumor represented by surface markers like CD133. These cells are responsible not only for tumor recurrence, but also poor prognosis based on their "stem-like" characteristics. At present, conventional therapy is directed towards rapidly dividing PDAC cells and thus fails to target the CSC population.. MIA PaCa-2, S2-013 and AsPC-1 were treated with 12.5 nM triptolide (12 T cells) for 7 days. The surviving cells were recovered briefly in drug-free growth media and then transferred to Cancer Stem cell Media (CSM). As a control, untreated cells were also transferred to CSM media (CSM). The 12 T and CSM cells were tested for stemness properties using RNA and protein markers. Low numbers of CSM and 12 T cells were implanted subcutaneously in athymic nude mice to study their tumorigenic potential. 12 T and CSM cells were sorted for CD133 expression and assayed for their colony forming ability and sphere forming ability. Invasiveness of 12 T cells, CSM and MIA PaCa-2 were compared using Boyden chamber assays.. Treated 12 T cells displayed increased expression of the surface marker CD133 and the drug transporter ABCG2 compared to untreated cells (CSM cells). Both 12 T and CSM cells formed subcutaneous tumors in mice confirming their tumor-initiating properties. When tested for invasion, 12 T cells had increased invasiveness compared to CSM cells. CD133(+) cells in both CSM and 12 T showed greater colony and sphere forming ability compared to CD133(-) cells from each group. Consistent with these data, when injected subcutaneously in mice, CD133(-) cells from CSM or 12 T did not form any tumors whereas CD133(+) cells from both groups showed tumor formation at a very low cell number. Despite pre-exposure to triptolide in 12 T CD133(+) cells, treatment of tumors formed by these cells with Minnelide, a triptolide pro-drug, showed significant tumor regression.. Our results indicated that triptolide enhanced and enriched the "stemness" in the PDAC cell lines at a low dose of 12.5 nM, but also resulted in the regression of tumors derived from these cells.

Topics: AC133 Antigen; Antigens, CD; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Survival; Diterpenes; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Epoxy Compounds; Glycoproteins; Humans; Neoplastic Stem Cells; Organophosphates; Pancreatic Neoplasms; Peptides; Phenanthrenes; Side-Population Cells

A new formulation of a natural product shows remarkable activity against pancreatic ductal adenocarcinoma across a number of preclinical model systems. These findings set the stage for a clinical trial.

Topics: Animals; Antineoplastic Agents, Alkylating; Carcinoma, Pancreatic Ductal; Clinical Trials as Topic; Diterpenes; Drug Evaluation, Preclinical; Epoxy Compounds; Humans; Medical Oncology; Medicine, Chinese Traditional; Organophosphates; Pancreatic Neoplasms; Phenanthrenes; Research Design; Translational Research, Biomedical