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
Cholangiocarcinoma (CCA) is at an advanced stage at the time of its diagnosis, and developing a more effective treatment of CCA would be desirable. Angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan may inhibit cancer cell proliferation, but the mechanisms by which telmisartan affects various cancers remain unknown. In this study, we evaluated the effects of telmisartan on human CCA cells and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on CCA cells using two cell lines, HuCCT-1 and TFK-1. In our experiments, telmisartan inhibited the proliferation of HuCCT-1 and TFK-1 cells. Additionally, telmisartan induced G0/G1 cell cycle arrest via blockade of the G0 to G1 cell cycle transition. Notably, telmisartan did not induce apoptosis in HuCCT-1 cells. This blockade was accompanied by a strong decrease in cell cycle-related protein, especially G1 cyclin, cyclin D1, and its catalytic subumits, Cdk4 and Cdk6. Telmisartan reduced the phosphorylation of EGFR (p-EGFR) and TIMP-1 by using p-RTK and angiogenesis array. Furthermore, miRNA expression was markedly altered by telmisartan in HuCCT-1. Telmisartan inhibits tumor growth in CCA xenograft model in vivo. In conclusion, telmisartan was shown to inhibit human CCA cell proliferation by inducing cell cycle arrest.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Benzoates/pharmacology , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Animals , Apoptosis/drug effects , Bile Duct Neoplasms/blood supply , Bile Duct Neoplasms/pathology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cholangiocarcinoma/blood supply , Cholangiocarcinoma/pathology , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/biosynthesis , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Random Allocation , Resting Phase, Cell Cycle/drug effects , Telmisartan , Xenograft Model Antitumor AssaysABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related death. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human HCC and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on HCC cells using the HLF, HLE, HepG2, HuH-7 and PLC/PRF/5 cell lines. In our experiments, telmisartan inhibited the proliferation of HLF, HLE and HepG2 cells, which represent poorly differentiated types of HCC cells. However, HuH-7 and PLC/PRF/5 cells, which represent well-differentiated types of HCC cells, were not sensitive to telmisartan. Telmisartan induced G0/G1 cell cycle arrest of HLF cells by inhibiting the G0-to-G1 cell cycle transition. This blockade was accompanied by a marked decrease in the levels of cyclin D1, cyclin E and other cell cycle-related proteins. Notably, the activity of the AMP-activated protein kinase (AMPK) pathway was increased, and the mammalian target of rapamycin (mTOR) pathway was inhibited by telmisartan treatment. Additionally, telmisartan increased the level of caspase-cleaved cytokeratin 18 (cCK18), partially contributed to the induction of apoptosis in HLF cells and reduced the phosphorylation of ErbB3 in HLF cells. Furthermore, miRNA expression was markedly altered by telmisartan in vitro. In conclusion, telmisartan inhibits human HCC cell proliferation by inducing cell cycle arrest.
Subject(s)
Benzimidazoles/pharmacology , Benzoates/pharmacology , Carcinoma, Hepatocellular/genetics , Cell Proliferation/drug effects , Liver Neoplasms/genetics , Carcinoma, Hepatocellular/drug therapy , Cell Cycle Checkpoints , Cell Cycle Proteins/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , MicroRNAs/genetics , TelmisartanABSTRACT
Liver metastasis from gastrointestinal cancer defines a patient's prognosis. Despite medical developments, pancreatic cancer with liver metastasis confers a very poor prognosis. Galectin-9 (Gal9) is a tandem-repeat-type galectin that has recently been demonstrated to exert antitumor effects on various types of cancer cells by inducing apoptosis. However, the apoptotic pathway of Gal9 in solid tumors is unclear. The aim of the present study was to evaluate the effects of Gal9 on human liver metastasis from pancreatic cancer. Gal9 suppressed cell proliferation in metastatic liver cancer cell lines derived from pancreatic cancer (KMP2, KMP7, and KMP8) and increased the levels of caspase-cleaved keratin 18 and fluorescein isothiocyanate (FITC)-conjugated Annexin V. Furthermore, expression of apoptosis-related molecules such as caspase-7, cleaved caspase-3, cleaved PARP, cytochrome c, Smac/Diablo and HtrA2/Omi was enhanced. However, Gal9 did not affect expression of various cell cycle-related proteins. The microRNA (miRNA) expression profile was markedly altered by Gal9, and various miRNAs might contribute to tumor growth suppression. Our data reveal that Gal9 suppresses the growth of liver metastasis, possibly by inducing apoptosis through a mechanism involving mitochondria and changes in miRNA expression. Thus, Gal9 might serve as a therapeutic agent for the treatment of liver metastasis from pancreatic cancer.
Subject(s)
Galectins/genetics , Liver Neoplasms/genetics , Neoplasm Proteins/genetics , Pancreatic Neoplasms/genetics , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Galectins/antagonists & inhibitors , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/pathology , Liver Neoplasms/secondary , MicroRNAs/genetics , Mitochondria/genetics , Mitochondria/pathology , Neoplasm Metastasis , Pancreatic Neoplasms/pathologyABSTRACT
Small bowel adenocarcinoma (SBAC) accounts for 3% of all gastrointestinal tract tumors and approximately 0.5% of all cancer cases. Recent studies have indicated that the use of metformin, one of the most commonly prescribed antidiabetic drugs, is associated with a better prognosis for certain malignant diseases. However, there have been no reports on the effect of metformin in SBAC. In the present study, we evaluated the effect of metformin on human SBAC cell proliferation in vitro and in vivo and identified the microRNAs (miRNAs) associated with its antitumor effects. Metformin inhibited the proliferation of HuTu80 cells in a time- and dose-dependent manner. Importantly, metformin reduced the expression of cyclin D1, cyclin E, cyclin-dependent kinase 4, and phosphorylated retinoblastoma protein, which resulted in cell cycle arrest at the G0/G1 phase. This arrest was accompanied by activation of AMPKα and inhibition of mammalian target of rapamycin and p70s6k. Additionally, metformin reduced the levels of phosphorylated epidermal growth factor receptor and ROR2 as well as markedly altered miRNA expression in HuTu80 cells. Metformin also inhibited tumor growth in vivo in a xenograft mouse model. Our data suggest that metformin might have therapeutic potential in SBAC.
Subject(s)
Adenocarcinoma/drug therapy , Gastrointestinal Neoplasms/drug therapy , Metformin/administration & dosage , Neoplasm Proteins/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin D1 , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Phosphorylation , Xenograft Model Antitumor AssaysABSTRACT
Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over a century. Recently, galectin-9, which has two distinct carbohydrate recognition domains connected by a linker peptide, was noted to induce apoptosis in thymocytes and immune cells. The apoptosis of these cells contributes to the development and regulation of acquired immunity. Furthermore, human recombinant galectin-9, hG9NC (null), which lacks an entire region of the linker peptide, was designed to resist proteolysis. The hG9NC (null) has demonstrated anti-cancer activities, including inducing apoptosis in hematological, dermatological and gastrointestinal malignancies. In this review, the molecular characteristics, history and apoptosis-inducing potential of galectin-9 are described.
