Defining Parallels between the Salivary Glands and Pancreas to Better Understand Pancreatic Carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a dismal prognosis, largely due to its late presentation. Methods for early detection, the development of reliable screening tools, and the identification of sensitive and specific biomarkers have remained essential research priorities to improve early patient management and outcomes. The pancreas and salivary glands share histological and functional similarities, and the salivary glands have a demonstrated a role in oral and systemic health. This review focuses on the similarities and differences between the pancreas and salivary glands and how these can inform our understanding of PDAC genesis and early diagnosis. In particular, chemical exposure, which alters salivary gland gene transcription and morphogenesis, may not only directly impact salivary gland regulation but alter pancreatic function via the systemic secretion of growth hormones. Diabetes and obesity are associated with an increased risk of pancreatic cancer, and a link between chemical exposure and the development of diabetes, obesity, and consequently PDAC genesis is proposed. Possible mechanisms include altering salivary or pancreatic morphology and organ function, disrupting endocrine signaling, or altering pro-inflammatory homeostasis. Finally, saliva contains putative specific biomarkers that show promise as non-invasive diagnostic tools for PDAC.

The Impact of Nutrition and Environmental Epigenetics on Human Health and Disease.

Environmental epigenetics describes how environmental factors affect cellular epigenetics and, hence, human health. Epigenetic marks alter the spatial conformation of chromatin to regulate gene expression. Environmental factors with epigenetic effects include behaviors, nutrition, and chemicals and industrial pollutants. Epigenetic mechanisms are also implicated during development in utero and at the cellular level, so environmental exposures may harm the fetus by impairing the epigenome of the developing organism to modify disease risk later in life. By contrast, bioactive food components may trigger protective epigenetic modifications throughout life, with early life nutrition being particularly important. Beyond their genetics, the overall health status of an individual may be regarded as an integration of many environmental signals starting at gestation and acting through epigenetic modifications. This review explores how the environment affects the epigenome in health and disease, with a particular focus on cancer. Understanding the molecular effects of behavior, nutrients, and pollutants might be relevant for developing preventative strategies and personalized heath programs. Furthermore, by restoring cellular differentiation, epigenetic drugs could represent a potential strategy for the treatment of many diseases including cancer.

Histone Deacetylase Inhibition Restores Expression of Hypoxia-Inducible Protein NDRG1 in Pancreatic Cancer.

OBJECTIVES: N-myc downstream-regulated gene-1 (NDRG1) is a hypoxia-inducible and differentiation-related protein and candidate biomarker in pancreatic cancer. As NDRG1 expression is lost in high-grade tumors, the effects of the differentiating histone deacetylase inhibitor trichostatin A (TSA) were examined in human pancreatic cancer cell lines representing different tumor grades. METHODS: PANC-1 (poorly differentiated) and Capan-1 (moderately to well-differentiated) cells were treated with TSA. Effects were assessed in vitro by microscopic analysis, colorimetric assays, cell counts, real-time polymerase chain reaction, and Western blotting. RESULTS: Treatment of PANC-1 cells over 4 days with 0.5 µM TSA restored cellular differentiation, inhibited proliferation, and enhanced p21 protein expression. Trichostatin A upregulated NDRG1 mRNA and protein levels under normoxia from day 1 and by 6-fold by day 4 (P < 0.01 at all time points). After 24 hours under hypoxia, NDRG1 expression was further increased in differentiated cells (P < 0.01). Favorable changes were identified in the expression of other hypoxia-regulated genes. CONCLUSIONS: Histone deacetylase inhibitors offer a potential novel epidrug approach for pancreatic cancer by reversing the undifferentiated phenotype and allowing patients to overcome resistance and better respond to conventional cytotoxic treatments.

Hypoxia increases cytoplasmic expression of NDRG1, but is insufficient for its membrane localization in human hepatocellular carcinoma.

NDRG1 is a hypoxia-inducible protein, whose modulated expression is associated with the progression of human cancers. Here, we reveal that NDRG1 is markedly upregulated in the cytoplasm and on the membrane in human hepatocellular carcinoma (HCC). We demonstrate further that hypoxic stress increases the cytoplasmic expression of NDRG1 in vitro, but does not result in its localization on the plasma membrane. However, grown within an HCC-xenograft in vivo, cells express NDRG1 in the cytoplasm and on the plasma membrane. In conclusion, hypoxia is a potent inducer of NDRG1 in HCCs, albeit requiring additional stimuli within the tumour microenvironment for its recruitment to the membrane.

Inhibition of hepatic tumor cell proliferation in vitro and tumor growth in vivo by taltobulin, a synthetic analogue of the tripeptide hemiasterlin.

AIM: To investigate the inhibitory effects of taltobulin (HTI-286), a synthetic analogue of natural hemiasterlin derived from marine sponges, on hepatic tumor growth in vitro and in vivo. METHODS: The potential anti-proliferative effects of HTI-286 on different hepatic tumor cell lines in vitro and in vivo were examined. RESULTS: HTI-286 significantly inhibited proliferation of all three hepatic tumor cell lines (mean IC50 = 2 nmol/L +/- 1 nmol/L) in vitro. Interestingly, no decrease in viable primary human hepatocytes (PHH) was detected under HTI-286 exposure. Moreover, intravenous administration of HTI-286 significantly inhibited tumor growth in vivo (rat allograft model). CONCLUSION: HTI-286 might be considered a potent promising drug in treatment of liver malignancies. HTI-286 is currently undergoing clinical evaluation in cancer patients.

ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: rational basis for a new combination therapy with capecitabine.

PURPOSE: The efficacy of new oral fluoropyrimidines, including capecitabine, is improved in cells expressing high levels of thymidine phosphorylase (TP) and low levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase. We used a human head and neck cancer cell line (CAL33) to examine the influence of cell cycle modifications on TS, TP, and dihydropyrimidine dehydrogenase activity. EXPERIMENTAL DESIGN: Cells were exposed to the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa(2)) and 5'-deoxy-5-fluorouridine (5'-DFUR), alone and in combination, for up to 96 h, and modifications in cell cycle, enzyme activity, and gene expression were examined. RESULTS: ZD1839 (24- to 72-h exposure) markedly reduced proliferation and caused a rapid increase in G(0)-G(1) and a decrease in S phase; a 40-fold decrease in TS activity at 24 h and a 2.5-fold increase in TP activity at 48 h were observed. A significant link between TP activity and expression was observed (r(2) = 0.98; P = 0.0068). Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839. Dose-effect curves of ZD1839 and 5'-DFUR, alone and in combination, were examined. Combination indices for ZD1839 + 5'-DFUR were 0.58 +/- 0.1 and 0.63 +/- 0.1 for 50% survival and 25% survival, respectively. Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839. CONCLUSIONS: These data demonstrate a strong synergistic interaction between ZD1839 and 5'-DFUR when ZD1839 is applied before or concurrently with 5'-DFUR. Such a drug combination would have two advantages: (a) the theoretical advantage of tumor selectivity of epidermal growth factor receptor-targeted therapy; and (b) the practical advantage of a combination therapy that could be administered p.o.