Our major translational goal is to develop a chemopreventive strategy for inhibiting progression of Barrett's esophagus to esophageal adenocarcinoma. We hypothesize that the deleterious effects of hydrophobic bile acids and low pH may be inhibited by the cytoprotective bile acid, ursodeoxycholic acid (UDCA), that was shown to protect cells against oxidative injury. The central hypothesis to be tested in this proposal is that bile acids in combination with low pH induce oxidative stress that leads to DMA damage, genomic instability and apoptosis resistance in Barrett's esophagus. Therefore, an alteration of bile acid composition by ursodeoxycholic acid treatment may be beneficial to Barrett's esophagus patients in the prevention of neoplastic progression.
Three specific aims are proposed to test this hypothesis. First, we will evaluate the effect of a bile acid cocktail and/or low pH on the generation of reactive oxygen species (ROS), oxidative, DNA damage, expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins in vitro in esophageal cell lines and ex vivo, in BE biopsies. We will determine the effect of acute, repeated and chronic exposure to bile acids and/or low pH (1) on the induction of superoxide, (2) formation of 8-OH-dG, a marker of oxidative DNA damage, (3) expression of DNA repair proteins (i.e. Mlh1, Pms2 and PARP), anti-oxidant (i.e. superoxide dismutases and catalase) and anti-apoptotic proteins (i.e. Mcl-1, survivin, Bcl-xL). Furthermore, we plan to identify patterns of DNA alterations using microarray-based comparative genomic hybridization (CGH) in novel esophageal cell lines developed for resistance to bile acids and/or low pH.
In specific aim #2 we plan to evaluate the effects of UDCA and its conjugated forms [(tauro-ursodeoxycholic acid (TUDCA), glyco- ursodeoxycholic acid (GUDCA)] on ROS production, oxidative DNA damage, genomic instability and the expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins induced by low pH and cytotoxic bile acids in vitro. Since UDCA is an excellent scavenger of ROS we anticipate that UDCA will reduce damage caused by bile acids and low pH. Finally, in specific aim #3 we propose to conduct a pilot clinical trial to evaluate UDCA as a potential preventive agent that changes the composition of bile acids in the refluxate so that less toxic bile acids are refluxed to the esophagus. Thus, bile acid composition at the baseline and post UDCA treatment will be determined. Furthermore, markers of oxidative stress (8-OH-dG) and proliferation (Ki-67) will be assessed in BE biopsies at the baseline, 6 months on UDCA and 6 months after discontinuation of UDCA using immunohistochemistry in conjunction with image analysis. Our long-term goal is to evaluate factors and molecular mechanisms leading to BE development and/or progression to esophageal adenocarcinoma and to inhibit these processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA095060-08
Application #
7799143
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$335,417
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Goldenberg, Joshua M; Pagel, Mark D; Cárdenas-Rodríguez, Julio (2018) Characterization of D-maltose as a T2 -exchange contrast agent for dynamic contrast-enhanced MRI. Magn Reson Med 80:1158-1164
Jones, Kyle M; Pollard, Alyssa C; Pagel, Mark D (2018) Clinical applications of chemical exchange saturation transfer (CEST) MRI. J Magn Reson Imaging 47:11-27
Goldenberg, Joshua M; Cárdenas-Rodríguez, Julio; Pagel, Mark D (2018) Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI. Mol Imaging Biol 20:575-583
Daryaei, Iman; Randtke, Edward A; Pagel, Mark D (2017) A biomarker-responsive T2exMRI contrast agent. Magn Reson Med 77:1665-1670
Daryaei, Iman; Jones, Kyle M; Pagel, Mark D (2017) Detection of DT-diaphorase Enzyme with a ParaCEST MRI Contrast Agent. Chemistry 23:6514-6517
Shkreta, Lulzim; Blanchette, Marco; Toutant, Johanne et al. (2017) Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication. Nucleic Acids Res 45:4051-4067
Fernández-Cuervo, Gabriela; Sinharay, Sanhita; Pagel, Mark D (2016) A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities. Chembiochem 17:383-7
Fernández-Cuervo, Gabriela; Tucker, Kirsten A; Malm, Scott W et al. (2016) Diamagnetic Imaging Agents with a Modular Chemical Design for Quantitative Detection of ?-Galactosidase and ?-Glucuronidase Activities with CatalyCEST MRI. Bioconjug Chem :
Liu, Lin; Messer, Karen; Baron, John A et al. (2016) A prognostic model for advanced colorectal neoplasia recurrence. Cancer Causes Control 27:1175-85
Harpel, Kaitlin; Leung, Sarah; Rice, Photini Faith et al. (2016) Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. Phys Med Biol 61:N60-9

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