digoxin and Pancreatic-Neoplasms

Digoxin affects several cellular pathways involved in tumorigenesis. We sought to determine the association between digoxin use and pancreatic cancer risk and survival.. A nested case-control study using The Health Improvement Network (THIN), a population-representative database from the United Kingdom (UK). Cases included all individuals with incident diagnosis of pancreatic cancer. Each case was matched to up to four controls using incidence density sampling based on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was digoxin therapy before cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between digoxin use and pancreatic cancer risk were estimated using conditional logistic regression. We further conducted a retrospective cohort study among pancreatic cancer cases using Cox regression model in order to evaluate the association between digoxin use and overall survival.. We identified 4,113 cases with incident pancreatic cancer and 16,072 matched controls. The adjusted OR for diagnosis of pancreatic cancer among active digoxin users was 1.41 (95% CI 1.16-1.72). The risk did not change among active users with duration of therapy of more than 1 year (adjusted OR of 1.39, 95% CI 1.11-1.76). Digoxin was not associated with change in overall survival with an adjusted hazard ratio of 0.97 (95% CI 0.81-1.18).. Digoxin use was associated with modestly increased pancreatic cancer risk but did not affect overall survival.

Topics: Aged; Digoxin; Female; Humans; Incidence; Logistic Models; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Risk Factors; United Kingdom

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Digoxin; Drug Combinations; Drug Repositioning; Drug Synergism; High-Throughput Screening Assays; Homeodomain Proteins; Humans; Male; Metformin; Mice; Molecular Targeted Therapy; Pancreatic Neoplasms; Simvastatin; Survivin; Trans-Activators

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

Topics: Carbon; Deoxycytidine; Digoxin; Drug Resistance, Neoplasm; Gemcitabine; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mucin-1; Pancreatic Neoplasms; Pentose Phosphate Pathway; Prognosis; Pyrimidines; Signal Transduction

Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

Topics: Adult; Aged; Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Digoxin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Middle Aged; Neoplasm Invasiveness; Neoplasm Transplantation; Pancreatic Neoplasms; Proto-Oncogene Proteins c-kit; Stem Cell Factor