Identification of Compound CB-2 as a Novel Late-Stage Autophagy Inhibitor Exhibits Inhibitory Potency against A549 Cells

Zhihui Liu; Lu Zhang; Yachao Liu; Hanxiao Zhang; Jingxuan Chen; Gaoqing Feng; Peichang Yang; Fangfang Sha; Liuqing Cui; Gangchun Sun

doi:10.3390/life11080865

Life (Aug 2021)

Identification of Compound CB-2 as a Novel Late-Stage Autophagy Inhibitor Exhibits Inhibitory Potency against A549 Cells

Zhihui Liu,
Lu Zhang,
Yachao Liu,
Hanxiao Zhang,
Jingxuan Chen,
Gaoqing Feng,
Peichang Yang,
Fangfang Sha,
Liuqing Cui,
Gangchun Sun

Affiliations

Zhihui Liu: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Lu Zhang: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Yachao Liu: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Hanxiao Zhang: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Jingxuan Chen: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Gaoqing Feng: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Peichang Yang: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Fangfang Sha: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Liuqing Cui: College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China
Gangchun Sun: College of Chemistry and Chemical Engineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China

DOI: https://doi.org/10.3390/life11080865
Journal volume & issue: Vol. 11, no. 8
p. 865

Abstract

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Autophagy has been recognized as a stress tolerance mechanism that maintains cell viability, which contributes to tumor progression, dormancy, and treatment resistance. The inhibition of autophagy in cancer has the potential to improve the therapeutic efficacy. It is therefore of great significance to search for new autophagy inhibitors. In the present study, after screening a series of curcumin derivatives synthesized in our laboratory, (E)-3-((E)-4-chlorobenzylidene)-5-((5-methoxy-1H-indol-3-yl)methylene)-1-methylpiperidin-4-one (CB-2) was selected as a candidate for further study. We found that CB-2 increased the LC3B-II and SQSTM1 levels associated with the accumulation of autophagosomes in non-small cell lung cancer (NSCLC) A549 cells. The increased level of LC3B-II induced by CB-2 was neither eliminated when autophagy initiation was suppressed by wortmannin nor further increased when autophagosome degradation was inhibited by chloroquine (CQ). CB-2 enhanced the accumulation of LC3B-II under starvation conditions. Further studies revealed that CB-2 did not affect the levels of the key proteins involved in autophagy induction but significantly blocked the fusion of autophagosomes with lysosomes. High-dose CB-2 induced the apoptosis and necrosis of A549 cells, while a lower dose of CB-2 mainly impaired the migrative capacity of A549 cells, which only slightly induced cell apoptosis. CB-2 increased the levels of mitochondrial-derived reactive oxygen species (ROS) while decreasing the mitochondrial membrane potential (MMP). Scavenging ROS via N-acetylcysteine (NAC) reversed CB-2-induced autophagy inhibition and its inhibitory effect against A549 cells. In conclusion, CB-2 serves as a new late-stage autophagy inhibitor, which has a strong inhibitory potency against A549 cells.

Published in Life

ISSN: 2075-1729 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science
Website: http://www.mdpi.com/journal/life

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