scholarly journals A mitophagy-mediated autophagy pathway that triggers apoptotic cell death in non-small cell lung cancer (NSCLC) for anticancer chemotherapy by Norcantharidin

Authorea ◽  
2020 ◽  
Author(s):  
jinyan zhu ◽  
Baoxia Li ◽  
Jinhua He ◽  
Qiuyun Luo ◽  
Liting Dai ◽  
...  
Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5849
Author(s):  
Hyo-Sun Gil ◽  
Jeong-Hun Lee ◽  
Ahmed K. Farag ◽  
Ahmed H. E. Hassan ◽  
Kyung-Sook Chung ◽  
...  

Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.


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