Study of the role of the Angiotensin II (Ang II) type 2 receptor (AT[subscript]2) in lung tumorigenesis

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Show simple item record Pickel, Lara Michelle 2008-05-15T21:41:42Z 2008-05-15T21:41:42Z 2008-05-15T21:41:42Z
dc.description.abstract Lung cancer mortality is the highest among all cancer–associated deaths. Despite early detection and treatment, prognosis of this disease remains poor. Therefore, development of new therapeutic agents and effective treatment procedures are urgently needed. Endogenous Angiotensin II (Ang II) type 2 receptor (AT[subscript]2), one of two isoforms of Ang II, has been shown to mediate apoptosis. Nanoparticle delivery systems make possible targeted drug delivery and controlled release of therapeutic molecules and genes. Thus, the aim of this study was to determine the anti-cancer effect of the over-expressed AT[subscript]2 gene on lung adenocarcinoma cells in vitro using adenoviral vector (Ad-) and nanoparticle (NP-) based gene delivery systems. This study showed that over-expression of Ad-AT[subscript]2 induced cancer cell-specific apoptosis in several human lung adenocarcinoma cell lines with minimal effect on normal lung epithelial cells. Ad-AT[subscript]2 significantly attenuated multiple human lung cancers' cell growth (A549 and H358) in vitro compared to the control viral vector, Ad-[Beta]-galactosidase (Ad-LacZ) when examined by direct cell count. The growth attenuation effect was detected as early as 24 hours after Ad-AT[subscript]2 transfection and lasted 12 days. Western Blot analysis revealed the activation of the caspase pathway. Examination for Annexin V by flow cytometry also confirmed activation of the apoptotic pathway via AT[subscript]2 over-expression. Similarly, AT[subscript]2 cDNA encapsulated poly(DL-lactide-co-glycolide) (PLGA) biodegradable nanoparticles (NPs) were shown to be effectively taken up into lung cancer cells. Surface conjugation of the angiotensin II peptide significantly stimulated uptake of the particles. This PLGA vector-dependent AT[subscript]2 transfection was effective in sustained gene expression and resultant cell death. These results indicate that the AT[subscript]2 over-expression effectively attenuated growth of lung adenocarcinoma cells through activation of intrinsic apoptosis. Since PLGA safety has been proven, whereas adenoviral vectors have several drawbacks in safety, the Ang II conjugated PLGA nanoparticles may be a better therapeutic gene delivery system. Therefore, it is concluded that the discovery of AT[subscript]2 DNA encapsulated PLGA conjugated with the Ang II peptide is a potentially useful tool for lung cancer gene therapy. en
dc.description.sponsorship KSU Terry C. Johnson Center for Basic Cancer Research; KSU College of Veterinary Medicine Dean’s fund NIH grant P20 RR017686; Joan’s Legacy Foundation Research Grant en
dc.language.iso en_US en
dc.publisher Kansas State University en
dc.subject Lung cancer en
dc.subject Nanoparticle en
dc.subject Angiotensin II type 2 receptor en
dc.subject Adenovirus en
dc.title Study of the role of the Angiotensin II (Ang II) type 2 receptor (AT[subscript]2) in lung tumorigenesis en
dc.type Thesis en Master of Science en
dc.description.level Masters en
dc.description.department Department of Electrical and Computer Engineering en
dc.description.advisor Masaaki Tamura en
dc.description.advisor Steven Warren en
dc.subject.umi Biology, Molecular (0307) en 2008 en May en

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