digitoxin and Pancreatic-Neoplasms

Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Digitoxin; Humans; Pancreatic Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species

High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells.. We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice. During growth of human cancers in these mice, hprt-null murine stromal cells replace their human counterparts.. Pancreatic and ovarian cancers explanted from these mice were grown in selection media to produce pure human cancer cell lines. We screened one cell line with a 3,131-drug panel and identified 77 U.S. Food and Drug Administration (FDA)-approved drugs with activity, and two novel drugs to which the cell line was uniquely sensitive. Xenografts of this carcinoma were selectively responsive to both drugs.. Chemotherapy can be personalized using patient-specific cell lines derived in biochemically selectable mice.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cardiotonic Agents; Digitoxin; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Interleukin Receptor Common gamma Subunit; Male; Mice; Mice, Nude; Mice, SCID; Nogalamycin; Ovarian Neoplasms; Pancreatic Neoplasms; Precision Medicine; Stromal Cells; Tumor Cells, Cultured