Discovery of novel agents on spindle assembly checkpoint to sensitize vinorelbine-induced mitotic cell death against human non-small cell lung cancers
Journal
International Journal of Molecular Sciences
Journal Volume
21
Journal Issue
16
Pages
1-18
Date Issued
2020
Author(s)
Abstract
Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC. ? 2020 by the authors. Licensee MDPI, Basel, Switzerland.
SDGs
Other Subjects
9 methyl 6 n (2 norbornyl)adenine; alpha tubulin; amphotericin B; beta tubulin; carboxyfluorescein diacetate succinimidyl ester; caspase; caspase 3; caspase 7; caspase 9; cyclic GMP phosphodiesterase; cyclin A; cyclin B1; cyclin D1; cyclin dependent kinase 1; cyclin E; glyceraldehyde 3 phosphate dehydrogenase; histone; paclitaxel; phosphodiesterase V; polyvinylidene fluoride; propidium iodide; protein Bak; protein Bax; protein bcl 2; protein p53; PUMA protein; sildenafil; sulforhodamine B; tubulin; vinorelbine tartrate; antineoplastic agent; BUB1 protein, human; phosphodiesterase V; phosphodiesterase V inhibitor; protein serine threonine kinase; vinorelbine tartrate; A-549 cell line; antiproliferative activity; apoptosis; Article; cell cycle arrest; cell cycle progression; cell death; cell population; cell proliferation; cell viability; chemoluminescence; chromosome segregation; clonogenic assay; colony formation; comparative study; confocal microscopy; controlled study; DNA fragmentation; down regulation; drug mechanism; drug potentiation; enzyme activity; enzyme linked immunosorbent assay; flow cytometry; G2 phase cell cycle checkpoint; high performance liquid chromatography; human; human cell; IC50; immunofluorescence; kinetochore; M phase cell cycle checkpoint; metaphase anaphase transition; metastasis; mitosis spindle; NCI-H69 cell line; non small cell lung cancer; nonhuman; nuclear magnetic resonance spectroscopy; polymerization; propidium iodide assay; protein expression; protein phosphorylation; S phase cell cycle checkpoint; sequence alignment; synergistic effect; tubulin polymerization assay; upregulation; Western blotting; drug effect; gene expression regulation; genetics; M phase cell cycle checkpoint; microtubule; non small cell lung cancer; pathology; spindle apparatus; A549 Cells; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; M Phase Cell Cycle Checkpoints; Microtubules; Phosphodiesterase 5 Inhibitors; Protein-Serine-Threonine Kinases; Spindle Apparatus; Vinorelbine
Type
journal article