The low efficiency of conventional therapies in achieving long-term survival of patients with lung cancer calls for development
of novel treatment options. Although several genes have been ...investigated for their antitumor activities through gene delivery,
problems surrounding the methods used, such as efficiency, specificity, and toxicity, hinder application of such therapies
in clinical settings. Aerosol gene delivery as nonviral and noninvasive method for gene therapy may provide an alternative
for a safer and more effective treatment for lung cancer. In this study, imidazole ring-containing urocanic acid–modified
chitosan (UAC) designed in previous study was used as a gene carrier. The efficiency of UAC carrier in lungs was confirmed,
and the potential effects of the programmed cell death protein 4 ( PDCD4 ) tumor suppressor gene on three major pathways (apoptosis, cell cycle, and angiogenesis) were evaluated. Aerosol containing
UAC/PDCD4 complexes was delivered into K- ras null lung cancer model mice through the nose-only inhalation system developed by our group. Delivered UAC/PDCD4 complex facilitated
apoptosis, inhibited pathways important for cell proliferation, and efficiently suppressed pathways important for tumor angiogenesis.
In summary, results obtained by Western blot analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase–mediated
nick end labeling assay suggest that our aerosol gene delivery technique is compatible with in vivo gene delivery and can be applied as a noninvasive gene therapy. Mol Cancer Ther 2006;5(4):1041–9
Inorganic phosphate (Pi) plays a key role in diverse physiological functions. Recently, considerable progress has been made in our understanding of the function and regulation of the brain-specific ...sodium-dependent inorganic phosphate transporter 1 (NPT1), which is found to exist principally in cerebrum and cerebellum. The potential importance of Pi as a novel signaling molecule and the poor prognosis of diverse neurodegenerative diseases that involve brain-specific NPT1 have prompted us to define the pathways by which Pi affects mouse brain growth. A high phosphate diet caused an increase in serum Pi accompanied by a decrease in calcium, and a decrease in body weight coupled with a decreased relative weight of cerebellum. A high phosphate diet caused a significant increase in protein expression of NPT1, both in cerebrum and cerebellum. Additionally, the high phosphate diet increased Homo sapiens v-akt murine thymoma viral oncogene homolog 1 (Akt) phosphorylation at Ser473 in cerebrum and cerebellum, whereas suppression of Akt phosphorylation at Thr308 was observed only in cerebellum. Selective suppression of eukaryotic translation initiation factor-binding protein (eIF4E-BP1) in cerebrum was induced by high levels of Pi, which induced cap-dependent and cap-independent protein translation in cerebrum and cerebellum, respectively. Phosphorylation of extracellular regulated kinase 1 (ERK1) in comparison with that of ERK2 was significantly reduced in both cerebrum and cerebellum. High levels of Pi reduced protein expressions of proliferating cell nuclear antigen (PCNA) and cyclin D1 in cerebrum and cerebellum. In conclusion, the results indicate that high dietary Pi can perturb normal brain growth, possibly through Akt-ERK signaling in developing mice.
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