Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

摘要: Non-small cell lung cancer (NSCLC) accounts about 80% of all cancers. More than two-thirds NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities 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 line low PDE5 expression, used as model. potentiated vinorelbine-induced anti-proliferative apoptotic effects NCI-H460 cells. Vinorelbine induced tubulin acetylation Bub1-related kinase (BUBR1) phosphorylation, necessary component spindle assembly checkpoint. These effects, well BUBR1 cleavage, were substantially enhanced co-treatment YL-9. Several mitotic arrest signals under combinatory treatment vinorelbine YL-9, including increase abnormalities, increased cyclin B1 B-cell lymphoma 2 (Bcl-2) phosphorylation phosphoproteins. Moreover, also displayed synergistic combining induce apoptosis A549 cells which express PDE5. In conclusion. data suggest is agent amplifies through activation checkpoint cycle. shows potential for further development NSCLC.