phenanthrenes and Adenoma

Triptolide, an effective component derived from Tripterygium wilfordii, has been well recognized to process a broad-spectrum antitumor activities in various tumor types. However, the potential role of triptolide in pituitary adenomas remains unknown. The aim of this study was to investigate the precise role of triptolide and underlying mechanism in regulating pituitary adenoma cell viability, migration and invasion.. We use mouse pituitary adenoma cells (TtT/GF and AtT20 cells) as the experiment model and treated them with varying concentrations of triptolide. The corresponding inhibitory effects on cell viability, migration, invasion and apoptosis were examined respectively, and the underlying mechanism was determined by investigating ADAM12 (a disintegrin and metalloprotease 12)/EGFR signaling.. Triptolide significantly inhibited cell viability, migration and invasion in TtT/GF and AtT20 cells in a dose-dependent manner. Mechanistically, triptolide significantly reduced ADAM12 expression at protein levels and attenuated ADAM12/EGFR signaling. Meanwhile, triptolide treatment combined with ADAM12 silencing enhanced the suppression effects on cell viability, migration and invasion, and those effects were restored following ADAM12-rescued. Moreover, triptolide suppressed the tumorigenesis of TtT/GF and AtT20 cells in vivo.. Our research provides evidence that triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway. These findings suggest a potential role for triptolide in treating pituitary adenomas.

Topics: ADAM12 Protein; Adenoma; Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Movement; Cell Survival; Diterpenes; Epoxy Compounds; ErbB Receptors; Mice; Phenanthrenes; Pituitary Gland; Pituitary Neoplasms; Signal Transduction

Carnosol, a constituent of the herb, rosemary, has shown beneficial medicinal and antitumor effects. Using the C57BL/6J/Min/+ (Min/+) mouse, a model of colonic tumorigenesis, we found that dietary administration of 0.1% carnosol decreased intestinal tumor multiplicity by 46%. Previous studies showed that tumor formation in the Min/+ mouse was associated with alterations in the adherens junctions, including an increased expression of tyrosine-phosphorylated beta-catenin, dissociation of beta-catenin from E-cadherin, and strongly reduced amounts of E-cadherin located at lateral plasma membranes of histologically normal enterocytes. Here, we confirm these findings and show that treatment of Min/+ intestinal tissue with carnosol restored both E-cadherin and beta-catenin to these enterocyte membranes, yielding a phenotype similar to that of the Apc(+/+) wild-type (WT) littermate. Moreover, treatment of WT intestine with the phosphatase inhibitor, pervanadate, removed E-cadherin and beta-catenin from the lateral membranes of enterocytes, mimicking the appearance of the Min/+ tissue. Pretreatment of WT tissue with carnosol inhibited the pervanadate-inducible expression of tyrosine-phosphorylated beta-catenin. Thus, the Apc(Min) allele produces adhesion defects that involve up-regulated expression of tyrosine-phosphorylated proteins, including beta-catenin. Moreover, these data suggest that carnosol prevents Apc-associated intestinal tumorigenesis, potentially via its ability to enhance E-cadherin-mediated adhesion and suppress beta-catenin tyrosine phosphorylation.

Topics: Abietanes; Adenoma; Animals; beta Catenin; Cadherins; Cell Adhesion; Cell Membrane; Colonic Neoplasms; Cytoskeletal Proteins; Enterocytes; Female; Intestine, Small; Mice; Mice, Inbred C57BL; Phenanthrenes; Phosphorylation; Rosmarinus; Trans-Activators; Tyrosine; Vanadates

ATP-sensitive K+ (KATP) channels have been characterized in pituitary GH3 cells with the aid of the patch-clamp technique. In the cell-attached configuration, the presence of diazoxide (100 microM) revealed the presence of glibenclamide-sensitive KATP channel exhibiting a unitary conductance of 74 pS. Metabolic inhibition induced by 2,4-dinitrophenol (1 mM) or sodium cyanide (300 microM) increased KATP channel activity, while nicorandil (100 microM) had no effect on it. In the inside-out configuration, Mg-ATP applied intracellularly suppressed the activity of KATP channels in a concentration-dependent manner with an IC50 value of 30 microM. The activation of phospholipase A2 caused by mellitin (1 microM) was found to enhance KATP channel activity and further application of aristolochic acid (30 microM) reduced the mellitin-induced increase in channel activity. The challenging of cells with 4,4'-dithiodipyridine (100 microM) also induced KATP channel activity. Diazoxide, mellitin and 4,4'-dithiodipyridine activated the KATP channels that exhibited similar channel-opening kinetics. In addition, under current-clamp conditions, the application of diazoxide (100 microM) hyperpolarized the membrane potential and reduced the firing rate of spontaneous action potentials. The present study clearly indicates that KATP channels similar to those seen in pancreatic beta cells are functionally expressed in GH3 cells. In addition to the presence of Ca(2+)-activated K+ channels, KATP channels found in these cells could thus play an important role in controlling hormonal release by regulating the membrane potential.

Topics: 2,4-Dinitrophenol; Action Potentials; Adenoma; Adenosine Triphosphate; Animals; Aristolochic Acids; Calcium Chloride; Diazoxide; Disulfides; Enzyme Activation; Ion Transport; Magnesium; Melitten; Nicorandil; Phenanthrenes; Phospholipases A; Phospholipases A2; Pituitary Gland, Anterior; Pituitary Neoplasms; Potassium; Potassium Channels; Pyridines; Rats; Sodium Cyanide; Tumor Cells, Cultured

Cyclopenta[cd]pyrene (CPP) was a potent tumorigen when tested over a 5-fold dose range in the newborn mouse assay. A 20-fold increase in lung tumor multiplicity and a nearly 8-fold increase in tumor incidence was observed at the lowest total dose tested (1.55 mumol) with the dose-response relationship indicating a saturation of tumor multiplicity at approximately 7 tumors/animal. No liver nodules or lymphatic system tumors were noted. Analysis of dose-response data for benzo[a]-pyrene (BaP) and 6-nitrochrysene (6-NC) showed that tumor multiplicity for BaP also saturated at approximately 7 tumors/animal, whereas no similar saturation was found for 6-NC at up to 40 tumors/animal. Progression of lung adenomas to adenocarcinomas, as measured by the incidence of mice bearing malignant tumors, was essentially a linear function of dose. To facilitate comparison and maximize quantitative data obtainable from the newborn mouse assay-parameters were defined for tumor incidence (ED50), tumor multiplicity (TM1.0) and tumor malignancy (malignancy index). Values for the ED50 and TM1.0 were similar for the same compound and a tumorigenic potency series of 6-NC greater than BaP greater than CPP was obtained corresponding to a ratio of approximately 1:10-25:76.5-135, respectively. The malignancy index, however, indicated increased adenocarcinoma induction in the order CPP greater than 6-NC greater than BaP as expressed by the ratio 1:1.4:8.3, respectively.

Topics: Adenoma; Animals; Animals, Newborn; Benzo(a)pyrene; Biological Assay; Carcinogens; Chrysenes; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Phenanthrenes; Pyrenes; Skin Neoplasms

A newborn mouse (BLU:Ha) lung adenoma bioassay demonstrated that 6-nitrochrysene was a highly potent tumorigen. It induced 100% incidence of lung tumors and a 150-fold increase in their number (20.84 tumors/mouse) at the lowest dose level tested (total dose: 38.5 micrograms/mouse). 70% of the 6-nitrochrysene treated mice had malignant lung tumors (adenocarcinomas). Lymphomas and nodular hyperplasia of the liver were also observed in treated, but not control, animals. The tumorigenicity of 6-nitrochrysene relative to other polynuclear aromatic hydrocarbons and their mononitro-derivatives has been discussed.

Topics: Adenoma; Animals; Animals, Newborn; Carcinogens; Chrysenes; Dose-Response Relationship, Drug; Female; Liver; Lung Neoplasms; Male; Mice; Phenanthrenes

Topics: Adenoma; Animals; Animals, Newborn; Carcinogens; Chrysenes; Female; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Mice; Neoplasms, Experimental; Phenanthrenes; Pregnancy; Structure-Activity Relationship