ABSTRACT
The prognosis of gastric cancer (GC) remains poor due to clinical drug resistance, and novel drugs are urgently needed. Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. MTT and colony-formation assays and Hoechst 33342 staining were used to measure the cytotoxicity of CDDP and AdP in GC cells. Cell apoptosis was measured using an Annexin-V-FITC/PI dual staining assay. Western blot analysis was conducted to detect the expression of proteins in the PI3K/AKT signaling pathway and resistance-related markers. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells in a concentration- and time-dependent manner. AdP also suppressed cell invasion and migration. Additionally, AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) in the PI3K/AKT/ARNT signaling pathway, which promoted apoptosis and necrosis in GC cells. AdP promoted apoptosis in CDDP-resistant GC cells by suppressing the PI3K/AKT/ARNT signaling pathway and might be considered a candidate agent for the clinical treatment of cisplatin-resistant GC.
Subject(s)
Biomarkers, Tumor/genetics , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , Peptides , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Stomach Neoplasms/metabolism , Adult , Aged , Amino Acid Sequence , Animals , Apoptosis/drug effects , Biomarkers, Tumor/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Male , Mice , Middle Aged , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Accumulating evidence suggests that platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor(VEGF) play a role in the progression of pulmonary arterial hypertension (PAH).Since chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary arteries, which are histological hallmarks of PAH, we explored the role of the PDGF-BB/KLF4/VEGF signaling axis in the angiogenesis of pulmonary artery endothelial cells (PAECs). METHODS: Adult male Wistar rats were used to study hypoxia-induced or monocrotaline (MCT)-induced right ventricular (RV) remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV vessels were performed. RESULTS: The results revealed that both the PDGF receptor-tyrosine kinase inhibitor imatinib and the multi-targeted VEGF and PDGF receptor inhibit or sunitinib malate reversed hypoxia-induced increases in right ventricular systolic pressure (RVSP), right ventricular function and thickening of the medial walls. Mechanistically VEGF/VEGFR and PDGF/PDGFR formed a biological complex. We also showed that PDGF-BBincreasedKLF4 promoter activity transcriptionally activating VEGF expression, which regulates PAEC proliferation; migration; and the cell-cycle transition from G0/G1phase to S phase and G2/M-phase and eventually leads to PAEC angiogenesis Conclusion: Our study indicates that hypoxia-induced angiogenesis of PAECs is associated with increased levels of PDGF-BB/KLF4/VEGF, which contribute to pulmonary vascular remodeling. Overall, our study contributes to a better understanding of PAH pathogenesis.
Subject(s)
Kruppel-Like Transcription Factors/metabolism , Proto-Oncogene Proteins c-sis/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism , Animals , Becaplermin , Cell Hypoxia , Cell Movement/drug effects , Cell Proliferation , Endothelial Cells/cytology , Endothelial Cells/metabolism , G1 Phase Cell Cycle Checkpoints/drug effects , Imatinib Mesylate/pharmacology , Indoles/pharmacology , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/antagonists & inhibitors , Kruppel-Like Transcription Factors/genetics , Lung/diagnostic imaging , Male , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-sis/antagonists & inhibitors , Proto-Oncogene Proteins c-sis/genetics , Pulmonary Artery/cytology , Pyrroles/pharmacology , RNA Interference , Rats , Rats, Wistar , Signal Transduction/drug effects , Sunitinib , Up-Regulation/drug effects , Vascular Remodeling/drug effectsABSTRACT
Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of the secreted HSP70-targeted peptide APOPTIN derived from Apoptin to GBM tumors. We applied this therapy to GBM models using human U87MG glioma cells and GBM xenograft models in mice. In U87MG and U251MG cells, conditioned medium from AAV2-apoptin-derived peptide (ADP)-expressing cells induced 83% and 78% cell death. In mice bearing intracranial U87MG tumors treated with AAV2-ADP, treatment resulted in a significant decrease in tumor growth and longer survival in mice bearing orthotopic invasive GBM brain tumors. These data indicate that ssAAV2-ADP injection in the left hemisphere effectively prevented ipsilateral tumor growth but was insufficient to prevent distal tumor growth in the contralateral hemisphere. However, the systemic route is the most effective approach for treating widely dispersed tumors. In summary, systemic delivery of AAV2-ADP is an attractive approach for invasive GBM treatment.
