ABSTRACT
Background: Pancreatic ductal adenocarcinoma (PDAC) is the most devastating of all cancers with an extremely poor prognosis. It has few effective and reliable therapeutic strategies. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). Telmisartan inhibits cancer cell proliferation, but the underlying mechanisms in PDAC, remain unknown. Material and Methods: In the present study, we evaluated the effects of telmisartan on human PDAC cell proliferation in vitro. We assessed the effects of telmisartan on human PDAC cells using the cell lines PK-1 and PANC-1. Results: Telmisartan inhibited the proliferation of these cells via blockade of the G0 to G1 cell cycle transition. This was accompanied by a strong decrease in cyclin D1. Telmisartan was also shown by receptor tyrosine kinase and angiogenesis arrays to reduce the phosphorylation of epidermal growth factor receptor (EGFR), and miRNA expression was markedly altered by telmisartan in PK-1 cells. Conclusion: In conclusion, telmisartan inhibits human PDAC cell proliferation by inducing cell cycle arrest. Furthermore, telmisartan significantly altered miRNA expression in vitro. Taken together, our study demonstrated the therapeutic potential of telmisartan and provides molecular mechanistic insights into its anti-tumor effect on PDAC cells.
Subject(s)
Carcinoma, Pancreatic Ductal , MicroRNAs , Pancreatic Neoplasms , Humans , Telmisartan/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Cell Line, Tumor , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Cell Proliferation , MicroRNAs/genetics , MicroRNAs/metabolism , Gene Expression Regulation, Neoplastic , Apoptosis , Pancreatic NeoplasmsABSTRACT
BACKGROUND/AIM: Gemcitabine, an inhibitor of DNA synthesis, is the gold standard chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miRNAs) play critical roles in cancers, including PDAC. However, less is known about the effect of gemcitabine on PDAC cells and miRNA expression in PDAC. We evaluated the effect of gemcitabine on the cell cycle of PDAC cells in vitro and in vivo and on the miRNA expression profile. MATERIALS AND METHODS: Effects of gemcitabine on PK-1 and PK-9 cell growth were evaluated using a cell counting kit-8 assay. Xenografted mouse models were used to assess gemcitabine effects in vivo. RESULTS: Gemcitabine inhibited the proliferation and tumour growth of PK-1 cells, and induced S phase cell cycle arrest. Numerous miRNAs were altered upon gemcitabine treatment of PK-1 cells and xenograft models. CONCLUSION: Altered miRNAs may serve as potential therapeutic targets for improving the efficacy of gemcitabine in PDAC.
Subject(s)
MicroRNAs , Pancreatic Neoplasms , Animals , Apoptosis , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Deoxycytidine/analogs & derivatives , Mice , MicroRNAs/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
To facilitate efficient oxygen and nutrient delivery, blood vessels in the brain form three-dimensional patterns. However, little is known about how blood vessels develop stereographically in the neocortex and how they control the expansion and differentiation of neural progenitors during neocortical development. We show that highly vascularized and avascular regions are strictly controlled in a spatially and temporally restricted manner and are associated with distinct cell populations. Dividing basal progenitors and oligodendrocyte precursors preferentially contact honeycomb vessels, but dividing apical progenitors are localized in avascular regions without Flt1-positive endothelial cells but directly contact with sprouting neovascular tip cells. Therefore, not all blood vessels are associated equally with neural progenitors. Furthermore, a disruption of normal vascular patterning can induce abnormalities in neural development, whereas the impaired features of neural progenitors influenced angiogenesis patterning. These results indicate that close association between the nervous and vascular systems is essential for neocortex assembly.
