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The Turkish Journal of Gastroenterology... Feb 2024Pancreatic ductal adenocarcinoma is an extremely deadly type of cancer with a high metastatic potential. Genetic factors in cellular events play an important role in the...
BACKGROUND/AIMS
Pancreatic ductal adenocarcinoma is an extremely deadly type of cancer with a high metastatic potential. Genetic factors in cellular events play an important role in the emergence of this situation. One of these factors is Aurora kinase family members, which play a role in migration, invasion, and cell cycle. In this study, the expression of vascular endothelial growth factor gene, which plays a role in migration, metastasis, and angiogenesis, on cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells of danusertib, a pan-Aurora kinase inhibitor, was examined.
MATERIALS AND METHODS
The half maximal inhibitory concentration (IC50) value (400 nM) of danusertib in cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells was determined by the wound-healing test depending on the dose and time and migration with CIM-Plate 16 in the xCELLingence system. In addition, the effect of danusertib on migration was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method and vascular endothelial growth factor gene expression.
RESULTS
When the dose- and time-dependent danusertib-applied cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells were compared with the control group, it was observed that the wound formed did not close. In the xCELLigence system CIM-Plate 16 migration analysis, it was observed that migration was inhibited in the group administered danusertib in parallel with the wound dehiscence experiment. The gene expressions of vascular endothelial growth factor decreased 0.5-fold at the 24th hour and 0.3-fold at the 48th hour in the Danusertib-administered groups.
CONCLUSION
Danusertib, a pan-Aurora kinase inhibitor, is predicted to be used as a potential agent in pancreatic cancers due to its antitumor and anti-metastatic effect.
Topics: Humans; Vascular Endothelial Growth Factor A; Adenocarcinoma; Pancreatic Neoplasms; Cystic Fibrosis; Aurora Kinases; Protein Kinase Inhibitors; Cell Proliferation; Benzamides; Pyrazoles
PubMed: 38454247
DOI: 10.5152/tjg.2024.22319 -
Biochemical Pharmacology May 2024Aurora kinase (AURK) and heat shock factor 1 (HSF1) are commonly overexpressed in non-small cell lung cancer (NSCLC), correlating with poor prognosis. This study aims to...
Aurora kinase (AURK) and heat shock factor 1 (HSF1) are commonly overexpressed in non-small cell lung cancer (NSCLC), correlating with poor prognosis. This study aims to assess the therapeutic potential of combining the Danusertib (Danu, AURK inhibitor) and KRIBB11 (HSF1 inhibitor) for NSCLC treatment. The effects of this combination were investigated in A549 cells and a tumor xenograft mouse model. The findings demonstrate that concurrent administration of Danu and KRIBB11 effectively impedes cell proliferation, induces apoptosis, and triggers G2/M cell cycle arrest. Moreover, the combination treatment upregulates pro-apoptotic proteins (Cleaved-caspase3, Cleaved-PARP, and Bax) while downregulating anti-apoptotic proteins (Bcl-2), as well as G2/M-related proteins (CDC2 and cyclin B1). Additionally, the combination treatment elevates reactive oxygen species (ROS) levels, decreases mitochondrial membrane potential, and activates the DNA damage pathway. Interestingly, we discovered that the PI3K/AKT pathway is involved in mediating the effects of both Danu and KRIBB11. Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.
Topics: Humans; Animals; Mice; Carcinoma, Non-Small-Cell Lung; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Lung Neoplasms; Cell Proliferation; Protein Kinase Inhibitors; Apoptosis; Cell Line, Tumor; Aminopyridines; Benzamides; Indazoles; Pyrazoles
PubMed: 38521474
DOI: 10.1016/j.bcp.2024.116155