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.
Highlights
Lung carcinoma is one of the top leading causes for cancer death worldwide
Vinorelbine, a third-generation vinca alkaloid approved for non-small cell lung cancer (NSCLC) treatment by inhibiting microtubule dynamics, either monotherapy or combination with other cancer medications enhances the survival of patients with advanced NSCLC [1,2]
The inhibition of phosphodiesterase type 5 (PDE5)-dependent signaling has been claimed in decreasing cell migration and sensitizing apoptotic capability of anticancer medications through multiple pathways including an increase of reactive oxygen species (ROS) production, increased CD95-mediated apoptosis, enhanced endocytosis-mediated drug uptake and reduced CXCL16 expression and secretion [5,10,11]
Summary
Lung carcinoma is one of the top leading causes for cancer death worldwide. Based on histopathological classification, more than 80% of the lung cancer patients are categorized as non-small cell lung cancer (NSCLC) in which the survival rate is lower than 10% for late-stage patients. Vinorelbine, a third-generation vinca alkaloid approved for NSCLC treatment by inhibiting microtubule dynamics, either monotherapy or combination with other cancer medications enhances the survival of patients with advanced NSCLC [1,2]. Phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil and vardenafil) either mono-treatment or combination with cancer therapeutic drugs have been suggested to display anti-proliferative and apoptotic activities in vitro and suppress tumor growth in vivo against several cancers, such as prostate cancer, lung cancer, breast cancer, colon adenocarcinoma, neuroblastoma, and oral cancer [5,6,7,8,9]. The inhibition of PDE5-dependent signaling has been claimed in decreasing cell migration and sensitizing apoptotic capability of anticancer medications through multiple pathways including an increase of reactive oxygen species (ROS) production, increased CD95-mediated apoptosis, enhanced endocytosis-mediated drug uptake and reduced CXCL16 expression and secretion [5,10,11]. Phosphorylation of Bub1-related kinase (BUBR1, a key component of mitotic checkpoint for spindle assembly) [20], tubulin acetylation and cell cycle regulator proteins have been identified in the study to discover the sensitization mechanism in which the potential derivative drives
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.